CN104640851A - Bicyclic aza compounds as muscarinic M1 receptor agonists - Google Patents

Bicyclic aza compounds as muscarinic M1 receptor agonists Download PDF

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CN104640851A
CN104640851A CN201380048192.7A CN201380048192A CN104640851A CN 104640851 A CN104640851 A CN 104640851A CN 201380048192 A CN201380048192 A CN 201380048192A CN 104640851 A CN104640851 A CN 104640851A
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deuterated
methyl
octane
cyclobutyl
ethyl
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CN104640851B (en
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盖尔斯·艾伯特·布朗
朱莉·伊莱恩·坎斯菲尔德
迈尔斯·斯图尔特·康格里夫
马克·皮克沃斯
本杰明·杰拉尔德·特汉
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Heptares Therapeutics Ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
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    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
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    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Abstract

This invention relates to compounds (Formula (1)) that are agonists of the muscarinic M1 receptor and which are useful in the treatment of muscarinic M1 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula where R1-R5, X1, X2 and p are as defined herein.

Description

As the bicyclic azepine compound of muscarinic M1 receptor stimulant
The present invention relates to the new amide compound of a class, its salt, comprise their pharmaceutical composition and the purposes in human body therapy thereof.Particularly, the present invention is directed to a class amide compound, this kind of amide compound is muscarinic M1 receptor stimulant, and is therefore used for the treatment of alzheimer's disease, schizophrenia, cognitive disorder and other are by the receptor-mediated disease of this muscarinic M1 and treatment or ease the pain.
background of invention
Muscarinic acetylcholine receptor (mAChR) is the member of g protein coupled receptor superfamily, its mediation neurotransmitter acetylcholine effect in maincenter and peripheral nervous system.Five mAChR hypotypes are cloned, M 1to M 5.This M 1mAChR mainly postsynaptic expression in cortex, hippocampus, striatum and thalamus; M 2mAChR is mainly positioned at brain stem and thalamus, but be also positioned at cortex, hippocampus and striatum, wherein they reside in (people such as blue Mead (Langmead), 2008 British Clinical pharmacology magazines (Br J Pharmacol)) on cholinergic synapse end.But, M 2mAChR also expresses in heart tissue (wherein vagal innervation of their mediate cardiac) and in unstriated muscle and exocrine gland secondaryly.M 3mAChR expresses in CNS low relative levels, but in unstriated muscle and glandular tissue (such as sweat gland and sialisterium) wide expression people such as (, 2008 British Clinical pharmacology magazines) blue Meads.
Muscarinic acceptor (especially M in central nervous system 1mAChR) in the cognitive process that mediation is higher, keying action is being played.The disease (such as alzheimer's disease) relevant to cognitive disorder is along with the loss (people such as Sheldon Whitehouse (Whitehouse), 1982 science (Science)) of cholinergic neuron in basal forebrain.In schizophrenia (also being characterized by cognitive disorder), mAChR density in the prefrontal cortex of schizoid experimenter, hippocampus and caudate putamen reduces people such as (, 2002 molecule psychiatry (Mol Psychiatry)) Dien (Dean).In addition, in animal model, the blocking-up of central cholinergic system path or infringement cause dark cognitive defect, and nonselective mAChR antagonist has shown the plan psychosis effect in induction psychiatry patient.Cholinergic replacement therapy is to a great extent based on using acetylcholinesterase depressant to stop the decomposition of endogenous acetylcholine.These compounds show curative effect (resisting Symptomatic cognitive ability to decline) clinically, but cause dose-limiting side effect (to come from peripheral M 2and M 3the excitement of mAChR), comprise upset gastrointestinal peristalsis, bradyrhythmia, nausea and vomiting ( http:// www.drugs.com/pro/donepezil.html; http:// www.drugs.com/pro/rivastigmine.html).
Discovery work is in addition the direct M of target 1the discriminating of mAChR agonist, with the raising of target cognitive function.This kind of work causes the discriminating of a series of agonist, and these agonists are illustrated by compound such as xanomeline, AF267B, sabcomeline, Milameline and cevimeline.Many cognitive preclinical models camber in rodent and/or inhuman both primates in these compounds are shown effective.Milameline has shown the curative effect of the defect of antagonism tropine induction in rodentine activity and spatial memory; Sabcomeline shows curative effect in the visual object differentiation task of marmoset; And the defect of xanomeline mAChR antagonist induction in reversing cognitive performance in passive avoidance pattern.
Alzheimer's disease (AD) is modal neurodegenerative disorders (having 2,660 ten thousand people in the whole world in 2006), and it affects old man, causes profound memory loss and cognition dysfunction.The nosetiology of this disease is very complicated, but is characterized by two significant brain sequela: the gathering of the amyloid plaque be made up of amyloid-β peptide (A β) to a great extent and the neurofibrillary tangles formed by the τ-albumen of Hyperphosphorylationof.The gathering of A β is considered to the central feature in AD progress, and like this since, many generally acknowledged therapy current targeted inhibition A β for AD treatment produce.A β is derived from the proteolytic cleavage of film mating type amyloid precursor protein (APP).APP is by the processing of two approach, and these two approach are approach generated with short amyloid that non-short amyloid generates.The APP cracking undertaken by gamma-secretase is all common for two paths, but in the former, APP is by a kind of alpha-secretase enzymatic lysis, to produce solvable APP α.Cracking site in A β sequence, thus gets rid of its formation.But, in the approach that short amyloid generates, APP by beta-secretase cracking to produce solvable APP β and A β.In vitro study shows, and mAChR agonist can promote the processing of APP, towards the path that solvable non-short amyloid generates.In vivo study shows, mAChR agonist AF267B changes the disease sample pathology in 3xTgAD transgenic mice, this mouse is a kind of model (people such as Ka Kamo (Caccamo), 2006 neurones (Neuron)) of the different components of alzheimer's disease.Finally, show mAChR agonist cevimeline in patients with Alzheimer disease, provide reduction on the cerebrospinal fluid levels of little but significant A β, therefore potential disease modification curative effect people such as (, 2000 neurologicals (Neurol)) Buddhist nuns strange (Nitsch) is proved.
In addition, preclinical study illustrates, and mAChR agonist shows atypical major tranquilizer sample curve in a series of clinical front pattern.MAChR agonist xanomeline reverses the behavior that multiple Dopamine HCL drives, comprise the motion of amphetamines induction in rat, what in mouse, Apomorphine was induced climbs, and what in one-sided 6-OH-DA injury rats, dopamine agonist drove turns to the motion destabilization (without EPS possibility) with amphetamines induction in monkey.Also shown inhibit A10 (instead of A9) dopaminergic cell discharge and conditioned avoidance and induction of prefrontal cortex in rat and volt core (instead of striatum) c-fos expression.These data all imply atypical antipsychotic agent sample curve (Mil pricks people such as (Mirza), 1999 medicines for central nervous system comment (CNS Drug Rev)).
Xanomeline, sabcomeline, Milameline and cevimeline all develop into the different steps for treatment alzheimer's disease and/or schizoid clinical development.The II phase clinical study carried out with xanomeline proves that it resists the curative effect in different cognitive symptom territories, comprise the Behavioral interference illusion relevant with Ahl tribulus sea silent sickness (people such as Bai Dike (Bodick), 1997 neurological yearbooks (Arch Neurol)).Also in the small-sized II phase of schizophreniac is studied, have evaluated this compound, and give remarkable minimizing people such as (, 2008 American Psychiatric magazines (Am J Psych)) thank-you cards that (Shekhar) of positive and negative symptoms when compared with placebo.But, in all clinical studyes, show needle is to the unacceptable safety margin of cholinergic side effect for xanomeline mAChR agonists relevant with other, and these side effects comprise nauseating, gastrointestinal pain, diarrhoea, a large amount of perspire (excessive sweating), hypersialosis (excessive secretion saliva), faint and bradyrhythmia.
Muscarinic acceptor take part in maincenter and peripheral pain.Pain can be divided into three kinds of different types: acute, struvite and nervosa.Acute pain plays important provide protection in maintenance organism safe is from stimulation, and this stimulation may produce tissue injury, but needs post-operative pain to manage.Inflammatory pain can occur due to many reasons, these reasons comprise tissue injury, autoimmune response and pathogenic agent and invade, and are caused by the effect of inflammatory mediator such as neuropeptide and prostanoid (it causes neuronal inflammation and pain).Neuropathic pain feels relevant to the improper pain sexuality of non-painful stimuli.Neuropathic pain is correlated with from multiple different disease/wound, such as Spinal injury, multiple sclerosis, diabetes (diabetic neuropathy), virus infection (such as HIV or bleb).It is also very common in cancer, as the result of disease or the side effect of chemotherapy.The analgesia of multiple pain stage is crossed in the activation having shown muscarinic acceptor, by the acceptor in activation spinal cord and the higher pain center in brain.Increased the endogenous levels of vagusstoff by acetylcholinesterase depressant, shown with agonist or the muscarinic acceptor of allosteric modulators direct activation and there is analgesic activities.By contrast, block muscarinic acceptor with antagonist or use knock out mice and add pain sensitivity.D.F. luxuriant and rich with fragrance Reno difficult to understand (Fiorino) and M. add West Asia-Gu Ziman (Garcia-Guzman), 2012 evidences of having commented the effect of M1 acceptor in pain.
Recently, authenticated for M 1the compound of the peanut of the selectivity (be better than peripheral express mAChR hypotype) that the display of mAChR hypotype improves (people such as Bridges (Bridges), 2008 bioorganic chemistries and medical chemistry communication (Bioorg Med Chem Lett); The people such as Johnson (Johnson), 2010 bioorganic chemistries and medical chemistry communication; The people such as Ba Cike (Budzik), 2010ACS medical chemistry communication (ACS Med Chem Lett)).Although the antagonism M increased 3the selectivity level of mAChR hypotype, some in these compounds are at this hypotype and M 2significant agonist activity is maintained in both mAChR hypotypes.Herein, we describe and unexpectedly show for M 1the highly selective level of mAChR is (more than M 2and M 3receptor subtype) a series of compounds.
accompanying drawing
Compound of the present invention decreases the lethe of tropine induction with dose dependent fashion.Fig. 1 shows, and finds that example 9 isomer 2 has reversed the lethe of the tropine induction of this example with the approximate ED50 of about 10mg/kg (po) with dose dependent fashion.The effect of 30mg/kg is similar to the effect produced by the anticholinesterase E2020 (0.1mg/kg, ip) serving as positive control.
invention
The invention provides multiple compounds, these compounds have the activity as muscarinic M1 receptor stimulant.More specifically, the invention provides multiple compounds, these compounds represent for the selectivity of M1 acceptor relative to M2 and M3 receptor subtype.
Therefore, in first embodiment (embodiment 1.1), the invention provides the compound that one has chemical formula (1):
Or its a kind of salt, wherein:
P is 0,1 or 2;
X 1and X 2be saturated alkyl, these alkyl comprise five to nine carbon atoms altogether together, and link together like this to make with lower part:
Form the loop systems of two rings;
R 1a C 1-10non-aromatic alkyl, this non-aromatic alkyl is optionally replaced by one to six fluorine atoms, and wherein this alkyl one or two but be not that whole carbon atoms is optionally substituted by a heteroatoms, this heteroatoms is selected from O, N and S and oxidised form thereof;
R 2hydrogen or a C 1-10non-aromatic alkyl;
Or R 1and R 2be attached to them together with the nitrogen-atoms on it and form a non-aromatic heterocyclic with four to nine ring memberses, wherein this heterocycle optionally comprises the second heteroatoms that is selected from O, N and S and oxidised form thereof; And wherein this heterocycle is optionally selected from C by one to six 1-2the substituting group of alkyl, fluorine and cyano group replaces;
R 3be selected from hydrogen, halogen, cyano group, hydroxyl, C 1-3alkoxyl group and one are optionally by C that one to six fluorine atoms replace 1-5non-aromatic alkyl, and wherein this alkyl one or two but be not whole carbon atoms be optionally selected from O, N and S a heteroatoms substitute;
R 4a C 1-6non-aromatic alkyl, this non-aromatic alkyl is optionally replaced by one to six fluorine atoms, and wherein this alkyl one or two but be not that whole carbon atoms is optionally substituted by a heteroatoms, this heteroatoms is selected from O, N and S and oxidised form thereof; And
R 5it is fluorine.
Have the concrete of chemical formula (1) and preferred compound as in following examples 1.2 to 1.64 define:
1.2 a kind of compounds according to embodiment 1.1, wherein R 1a C comprising 0,1 or 2 carbon-to-carbon multiple bond 1-10non-aromatic alkyl, wherein this alkyl is optionally replaced by one to six fluorine atoms, and wherein this alkyl one or two but be not that whole carbon atoms is optionally substituted by a heteroatoms, this heteroatoms is selected from O, N and S and oxidised form thereof.
1.3 a kind of compounds according to any one of embodiment 1.1 and 1.2, wherein R 1be selected from C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl and by a C 3- 10cycloalkyl or C 5-6cycloalkenyl groups composition or comprise its C 1-10non-aromatic alkyl; Eachly in described alkyl, thiazolinyl, alkynyl and non-aromatic alkyl optionally to be replaced by one to six fluorine atoms, and wherein each one or two but be not that whole carbon atom is optionally substituted by a heteroatoms in these alkyl, thiazolinyl, alkynyl and non-aromatic alkyl, this heteroatoms is selected from O, N and S and oxidised form thereof.
1.4 a kind of compounds according to any one of embodiment 1.1 to 1.3, wherein R 1be selected from:
Optionally by the C of 1 to 6 fluorine atoms replacements 1-6alkyl;
Optionally by the methoxyl group-C of 1 to 6 fluorine atoms replacements 1- 4alkyl;
C 1-6alkoxyl group;
C 2-6thiazolinyl;
C 2- 6alkynyl;
Optionally by C that one or two methyl group replaces 3-6cycloalkyl;
C 4-5cycloalkyl-CH 2-, wherein this C 4-5cycloalkyl moiety is optionally by a C 1-2alkyl group replaces, and wherein this C 4-5a carbon atom of cycloalkyl moiety is optionally substituted by a Sauerstoffatom;
Cyclopropyl-C 1-3alkyl;
Cyclopentenyl; And
Methyl-two ring [2.2.2] octyl group.
1.5 a kind of compounds according to embodiment 1.4, wherein R 1be selected from:
Optionally by the C of 1 to 6 fluorine atoms replacements 1-6alkyl;
Optionally by C that one or two methyl group replaces 3-6cycloalkyl;
C 4-5cycloalkyl-CH 2-, wherein this C 4-5cycloalkyl moiety is optionally by a C 1-2alkyl group replaces, and wherein this C 4-5a carbon atom of cycloalkyl moiety is optionally substituted by a Sauerstoffatom;
Cyclopropyl-C 1-3alkyl; And
Methyl-two ring [2.2.2] octyl group.
1.6 a kind of compounds according to embodiment 1.5, wherein R 1optionally by the C of 1 to 6 fluorine atoms replacements 1- 6alkyl.
1.7 a kind of compounds according to embodiment 1.5, wherein R 1optionally by C that one or two methyl group replaces 3- 6cycloalkyl.
1.8 a kind of compounds according to embodiment 1.5, wherein R 1c 4- 5cycloalkyl-CH 2-, wherein this C 4-5cycloalkyl moiety is optionally by a C 1-2alkyl group replaces, and wherein this C 4-5a carbon atom of cycloalkyl moiety is optionally substituted by a Sauerstoffatom.
1.9 a kind of compounds according to embodiment 1.5, wherein R 1cyclopropyl-C 1-3alkyl.
1.10 a kind of compounds according to embodiment 1.5, wherein R 1it is methyl-two ring [2.2.2] octyl group.
1.11 a kind of compounds according to embodiment 1.4, wherein R 1be selected from following group A to AH:
Wherein asterisk represents that this group is attached to the point of this amide nitrogen atom.
1.12 a kind of compounds according to embodiment 1.11, wherein R 1be selected from group A, B, D, E, F, G, L, M, N, O, Q, R, T, V, W, Y, AB, AE, AF, AG and AH.
1.13 a kind of compounds according to any one of embodiment 1.1 to 1.4, wherein R 1be selected from 2-methyl-propyl; 2,2-dimethyl propyl; The tertiary butyl; 2-methyl-Ding-2-base; 2,3-dimethyl butyrate-2-base; Cvclopropvlmethvl; Cyclobutylmethyl; Cyclopentyl; Cyclopentyl-methyl; 1-methyl-cyclobutyl; 1-methylcyclopentyl; 1-methylcyclohexyl; 1-methylcyclopentylmethyl; Cyclopropyl-propyl-2-base; 1-methyl-cyclobutyl methyl, 1-ethyl-cyclobutyl methyl, 1-(methyl fluoride) cyclobutyl, 1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl and 1-(1,1, the deuterated methyl of 1-tri-)-2,2,3, the deuterated cyclobutyl group of 3,4,4-six.
1.14 a kind of compounds according to embodiment 1.13, wherein R 1be selected from 2-methyl-propyl and 1-methyl-cyclobutyl.
1.15 a kind of compounds according to embodiment 1.14, wherein R 1it is 2-methyl-propyl.
1.16 a kind of compounds according to embodiment 1.14, wherein R 1it is 1-methyl-cyclobutyl.
1.17 a kind of compounds according to any one of embodiment 1.1 to 1.16, wherein R 2be selected from hydrogen and C 1-6alkyl.
1.18 a kind of compounds according to embodiment 1.17, wherein R 2be selected from hydrogen, methyl, ethyl and sec.-propyl.
1.19 a kind of compounds according to embodiment 1.18, wherein R 2hydrogen.
1.20 a kind of compounds according to any one of embodiment 1.1 to 1.19, wherein R 3be selected from hydrogen, halogen, cyano group, hydroxyl, C 1-3alkoxyl group and C 1-4alkyl.
1.21 a kind of compounds according to embodiment 1.20, wherein R 3be selected from hydrogen, fluorine, methyl and methoxyl group.
1.22 a kind of compounds according to embodiment 1.21, wherein R 3be selected from hydrogen, fluorine and methoxyl group.
1.23 a kind of compounds according to embodiment 1.22, wherein R 3be selected from hydrogen and fluorine.
1.24 a kind of compounds according to embodiment 1.23, wherein R 3hydrogen.
1.25 a kind of compounds according to embodiment 1.23, wherein R 3it is fluorine.
1.26 a kind of compounds according to any one of embodiment 1.1 to 1.25, wherein R 4a non-annularity C 1-6alkyl.
1.27 a kind of compounds according to embodiment 1.26, wherein R 4a non-annularity C 1-3alkyl.
1.28 a kind of compounds according to embodiment 1.27, wherein R 4a C 1-3alkyl group or a C 2-3alkynyl group.
1.29 a kind of compounds according to embodiment 1.28, wherein R 4be selected from methyl, ethyl, ethynyl and 1-proyl.
1.30 a kind of compounds according to embodiment 1.29, wherein R 4it is methyl.
1.31 a kind of compounds according to any one of embodiment 1.1 to 1.30, wherein p is 0 or 1.
1.32 a kind of compounds according to embodiment 1.31, wherein p is 0.
1.33 a kind of compounds according to embodiment 1.31, wherein p is 1.
1.34 a kind of compounds according to any one of embodiment 1.1 to 1.33, wherein X 1and X 2comprise six or seven carbon atoms together.
1.35 a kind of compounds according to any one of embodiment 1.1 to 1.34, wherein by the loop systems of two rings formed with lower part:
It is the loop systems of two rings of a bridging.
1.36 a kind of compounds according to embodiment 1.35, wherein the bicyclic ring system of this bridging is an azabicyclo-octane or azabicyclo-nonane loop systems.
1.37 a kind of compounds according to embodiment 1.36, wherein the bicyclic ring system of this bridging is selected from 8-aza-bicyclo [3.2.1] octane loop systems, 9-aza-bicyclo [3.3.1] nonane loop systems and 6-aza-bicyclo [3.2.1] octane loop systems.
1.38 a kind of compounds according to embodiment 1.37, wherein the bicyclic ring system of this bridging is selected from following loop systems BA, BB and BC:
1.39 a kind of compounds according to embodiment 1.38, wherein the bicyclic ring system of this bridging is loop systems BA.
1.40 a kind of compounds according to embodiment 1.38, wherein the bicyclic ring system of this bridging is loop systems BB.
1.41 a kind of compounds according to embodiment 1.38, wherein the bicyclic ring system of this bridging is loop systems BC.
1.42 a kind of compounds according to any one of embodiment 1.1 to 1.34, wherein by the loop systems of two rings formed with lower part:
It is the loop systems of a volution.
1.43 a kind of compounds according to embodiment 1.42, wherein the loop systems of this volution is 2-aza-spiro [3.4] octane or 6-aza-spiro [3.4] octane loop systems.
1.44 a kind of compounds according to embodiment 1.43, wherein the loop systems of this volution is selected from following loop systems CA and CB:
1.45 a kind of compounds according to embodiment 1.44, wherein the loop systems of this volution is loop systems CA.
1.46 a kind of compounds according to embodiment 1.44, wherein the loop systems of this volution is loop systems CB.
1.47 a kind of compounds according to any one of embodiment 1.1 to 1.34, wherein by the loop systems of two rings formed with lower part:
It is the loop systems of two rings that condenses.
1.48 a kind of compounds according to embodiment 1.47, wherein this bicyclic ring system condensed is a pentamethylene pyrrolidine ring system.
1.49 a kind of compounds according to embodiment 1.47, wherein this pentamethylene pyrrolidine ring system has following structure DA
1.50 a kind of compounds according to any one of embodiment 1.1 to 1.34, wherein by the loop systems of two rings formed with lower part:
Be selected from:
(a) azabicyclo-octane or azabicyclo-nonane loop systems;
(b) 2-aza-spiro [3.4] octane or 6-aza-spiro [3.4] octane loop systems; And
(c) pentamethylene pyrrolidine ring system.
1.51 a kind of compounds according to embodiment 1.50, wherein by the loop systems of two rings formed with lower part:
Be selected from following loop systems BA, BB, BC, CA, CB and DA:
1.52 a kind of compounds according to embodiment 1.1, this compound has chemical formula (2):
Wherein R 1, R 3, R 4, R 5with p any one of embodiment 1.1 to 1.34 define; Q is 1,2 or 3, and r is 0 or 1, and condition is the summation of q and r is 2 or 3.
1.53 a kind of compounds according to embodiment 1.52, wherein (i) r is 0 and q is 2; (ii) r is 0 and q is 3; Or (iii) r is 1 and q is 1.
1.54 a kind of compounds according to embodiment 1.1, this compound has chemical formula (3):
Wherein R 1, R 3, R 4, R 5with p any one of embodiment 1.1 to 1.34 define; S is 0 or 1 and t is 0 or 1.
1.55. a kind of compound according to embodiment 1.54, wherein the summation of s and t is 1.
1.56 a kind of compounds according to embodiment 1.55, wherein s is 0, and t is 1.
1.57 a kind of compounds according to embodiment 1.55, wherein s is 1, and t is 0.
1.58 a kind of compounds according to embodiment 1.1, this compound has chemical formula (4):
Wherein R 1, R 3, R 4, R 5with p any one of embodiment 1.1 to 1.34 define; And u, v, w and x each naturally 0,1 or 2, condition is that the summation of u+v+w+x is at least 1 and is no more than 5.
1.59 a kind of compounds according to embodiment 1.58, wherein each in u, v, w and x is 1.
1.60 a kind of compounds according to embodiment 1.1, this compound any one of embodiment 1 to 13 define.
1.61 a kind of compounds according to any one of embodiment 1.1 to 1.60, this compound has the molecular weight being less than 550, such as, be less than 500, or is less than 450.
1.62 a kind of compounds according to any one of embodiment 1.1 to 1.61, this compound is in a kind of form of salt.
1.63 a kind of compounds according to embodiment 1.62, wherein this salt is a kind of acid salt.
1.64 a kind of compounds according to embodiment 1.62 or embodiment 1.63, wherein this salt is a kind of pharmacy acceptable salt.
definition
In this application, except as otherwise noted, application definition below.
The term " treatment " relevant to the purposes of the compound with chemical formula (1) is used to any type of intervention is described, is wherein given by a kind of compound just to meet with or risky experience or have potential risk to meet with the experimenter of disease or the obstacle discussed.Therefore, what term " treatment " was contained preventative (prophylactic) treatment and wherein shown this disease or obstacle measures the treatment that maybe can detect symptom.
As (such as relevant to the methods for the treatment of of a kind of disease or the patient's condition) used herein term " effective therapeutic dose " refers to effectively measuring producing desirable result for the treatment of of this compound.Such as, if this patient's condition is pain, so this treatment significant quantity is the amount of the pain relief being enough to provide desirable level.The pain relief of this desirable level can be, such as, remove this pain completely or reduce the severity of this pain.
In chemical formula (1), X 1and X 2be saturated alkyl, these alkyl comprise five to nine carbon atoms altogether together, and link together like this to make with lower part:
Form the loop systems of two rings.As used herein at X 1and X 2linguistic context under term " bicyclic ring system " comprise condense second cycle line system, bridging second cycle line system and comprise two volution systems of ring connected.
Term " non-aromatic alkyl " is (as at " C 1-10non-aromatic alkyl " or " non-annularity C 1-5in non-aromatic alkyl ") refer to one by carbon and hydrogen atom form and do not comprise the group of aromatic ring.This alkyl can be the completely saturated mixture that maybe can comprise one or more carbon-carbon double bond or carbon carbon triple bond or double bond and triple bond.This alkyl can be the group of a straight chain or side chain, or can form or comprise a cyclic group by a cyclic group.Therefore, term non-aromatic hydrocarbon comprises alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, cycloalkenyl alkyl etc.
Except as otherwise noted, term " alkyl ", " thiazolinyl ", " alkynyl ", " cycloalkyl " and " cycloalkenyl group " use (such as in the golden skin book of IUPAC define) with its conventional meaning.
As term used herein " cycloalkyl ", wherein permit the carbon atom specified number, comprise the group of naphthene base of monocycle, such as the group of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl and two rings and three rings.The group of naphthene base of two rings comprises the loop systems of bridging, such as norbornane, double-octane and diamantane.
At above R 1, R 3and R 4definition in, which illustrate this non-aromatic alkyl one or two but be not that whole carbon atom is optionally substituted by a heteroatoms, this heteroatoms is selected from O, N and S and (at R 1and R 4when) its oxidised form.At formation R 6this part R of part bdefinition in, this alkyl one or two but be not that whole carbon atom is optionally selected from the heteroatoms of O, N and S by one or is selected from CO, X by one 1c (X 2), C (X 2) X 1, SO and SO 2group substitute.To understand, when a carbon atom is substituted by a heteroatoms, mean compared with the atom be attached on replaced carbon atom compared to the heteroatoms of the lower chemical valence of carbon, less atom is attached on these heteroatomss.Such as, therefore, at a CH 2substitute a carbon atom (chemical formula is four) by oxygen (chemical valence is two) in group will mean, the molecule obtained will comprise two hydrogen atoms less, and at a CH 2substitute a carbon atom (chemical valence is four) by nitrogen (chemical valence is three) in group will mean, the molecule obtained will comprise a hydrogen atom less.
The example substituted for the heteroatoms of carbon atom is included in-a CH 2-CH 2-CH 2a carbon atom is substituted to provide a kind of ether-CH with oxygen or sulphur in-chain 2-O-CH 2-or thioether-CH 2-S-CH 2-, at a group CH 2a carbon atom is replaced to provide a kind of nitrile (cyano group) group CH with nitrogen in-C ≡ C-H 2-C ≡ N, at a group-CH 2-CH 2-CH 2-in replace a carbon atom to provide a kind of ketone-CH with C=O 2-C (O)-CH 2-, at a group-CH 2-CH 2-CH 2-in S=O or SO 2replace a carbon atom to provide a kind of sulfoxide-CH 2-S (O)-CH 2-or sulfone-CH 2-S (O) 2-CH 2-, at-a CH 2-CH 2-CH 2a carbon atom is replaced to provide a kind of acid amides-CH with C (O) NH in-chain 2-CH 2-C (O)-NH, at-a CH 2-CH 2-CH 2a carbon atom is replaced to provide a kind of amine-CH with nitrogen in-chain 2-NH-CH 2-, and at-a CH 2-CH 2-CH 2a carbon atom is replaced to provide a kind of ester (or carboxylic acid)-CH with C (O) O in-chain 2-CH 2-C (O)-O-.In each this type of substitutes, at least one carbon atom of this alkyl must be retained.
salt
Many compounds with chemical formula (1) can exist in a salt form, such as acid salt, or the salt of organic and mineral alkali in some cases, such as carboxylate salt, sulfonate and phosphoric acid salt.All this kind of salt within the scope of the invention, and to have chemical formula (1) compound mention comprise as in embodiment 1.62 to 1.64 the salt form of these compounds that defines.
These salt acid salt typically.
Salt of the present invention can by conventional chemical process (such as in pharmaceutical salts: characteristic, selection and purposes (Pharmaceutical Salts:Properties, Selection, and Use), P. Heinrichs Te Er (Heinrich Stahl) editor, Camille (Camille) G Wei Mut (Wermuth) (editor), ISBN:3-90639-026-8, hard front cover, 388 pages, method illustrated in 2002 8 months) from the parent compound synthesis comprising a kind of alkalescence or acidic moiety.Usually, this type of salt can by carrying out reacting preparing with suitable alkali or acid in water or in a kind of organic solvent or in the mixture of both by these compounds of free acid or alkali form; Usually, employ non-aqueous media, such as ether, ethyl acetate, ethanol, Virahol or acetonitrile.
Acid salt (as in embodiment 1.63 define) available diversified acid (inorganic and organic both) formed.The example falling into the acid salt of embodiment 1.63 comprises the list-or two-salt that are formed with a kind of acid being selected from the group be made up of the following: acetic acid, 2,2-dichloro acetic acid, hexanodioic acid, Lalgine, xitix (such as L-AA), L-Aspartic acid, Phenylsulfonic acid, phenylformic acid, 4-acetylamino benzoic acid, butyric acid, (+)-dextrocamphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, sad, styracin, citric acid, Cyclamic Acid, dodecyl sulphate, ethane-1,2-disulfonic acid, ethyl sulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, tetrahydroxyadipic acid, gentisinic acid, glucoheptonic acid, D-glyconic acid, glucuronic acid (such as D-Glucose aldehydic acid), L-glutamic acid (such as Pidolidone), α ketoglutaric acid, oxyacetic acid, urobenzoic acid, haloid acid (such as Hydrogen bromide, hydrochloric acid, hydroiodic acid HI), ethylenehydrinsulfonic acid, lactic acid (such as (+)-Pfansteihl, (±)-DL-LACTIC ACID), lactobionic acid, toxilic acid, oxysuccinic acid, (-)-L MALIC ACID, propanedioic acid, (±)-DL-amygdalic acid, methylsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, vitamin B13, oxalic acid, palmitinic acid, pamoic acid, phosphoric acid, propionic acid, pyruvic acid, L-Glutimic acid, Whitfield's ointment, 4-amino-salicylic, sebacic acid, stearic acid, succsinic acid, sulfuric acid, Weibull, (+)-L-TARTARIC ACID, thiocyanic acid, p-toluenesulphonic acids, undecylenic acid and valeric acid, together with acylated amino and Zeo-karb.
Wherein, these compounds with chemical formula (1) comprise an amine functional group, and these can form quaternary ammonium salt, and the method such as known according to those of ordinary skill in the art is by reacting with a kind of alkylating agent.This type of quaternary ammonium compound is in the scope of chemical formula (1).
These compounds of the present invention can exist for list-or two-salt, depend on the pKa of this acid (this salt is formed from it).
The salt form pharmacy acceptable salt typically of compound of the present invention, and the example of pharmacy acceptable salt is discussed at the people such as Berge (Berge), 1977, " pharmacy acceptable salt (Pharmaceutically Acceptable Salts) " pharmaceutical science magazine (J.Pharm.Sci.,) the 66th volume, in 1-19 page.But, not that pharmacy acceptable salt class also can be prepared as intermediate forms, then they can be converted into pharmacy acceptable salt class.Acceptable salt form in this kind of non-pharmaceutical, such as, or may be separated in compound of the present invention useful at purifying, also form part of the present invention.
steric isomer
Steric isomer is the molecule of isomery, and it has identical molecular formula and the sequence of bonded atom, but only its atom three-dimensional orientation is spatially different.This steric isomer can be, such as geometrical isomer or optical isomer.
geometrical isomer
With geometrical isomer, this isomery is directed about the difference of a double bond owing to an atom or group, as being in cis and trans (Z and E) isomery about a carbon-carbon double bond, or about cis and the trans-isomer(ide) of an amido linkage, or about the genial anteiso-structure of a carbon-to-nitrogen double bon (such as in an oxime), or about the rotational isomeric of a key that wherein there is restriction and rotate, or about the cis of a ring (such as a naphthenic hydrocarbon ring) and trans-isomerism.
Therefore, in another embodiment (embodiment 1.65), the invention provides the geometrical isomer of a kind of compound according to any one of embodiment 1.1 to 1.64.
optical isomer
The compound wherein with this chemical formula comprises one or more chiral centre, and can exist with the form of two or more optical isomers, mention that these compounds comprise its all optical isomeric form (such as enantiomer, epimer and diastereomer), for individual optical isomer or mixture (such as racemic mixture) or two or more optical isomers, unless the context otherwise requires.
Therefore, in another embodiment (embodiment 1.66), the invention provides a kind of compound according to any one of embodiment 1.1 to 1.65, this compound comprises a chiral centre.
These optical isomers can by its optical activity (namely, it is+He – isomer, or d and l isomer) characterize and differentiate, or they can use by Cann (Cahn) for its absolute stereochemical, " R and S " nomenclature that Ingold (Ingold) and Prey Lip river lattice (Prelog) are developed characterizes (see Advanced Organic Chemistry (Advanced Organic Chemistry), Jerry agate strange (Jerry March), 4th edition, John Willie father and son press (John Wiley & Sons), New York, 1992, 109-114 page, also see Cann, Ingold & Prey Lip river lattice, the English international version (Angew.Chem.Int.Ed.) 1966 of Germany's applied chemistry, 5, 385-415).Optical isomer is separated by multiple technologies (comprising chiral chromatography (chromatography on chiral support)), and this kind of technology is known to those skilled in the art.As the replacement scheme of chiral chromatography, optical isomer is separated by following: form diastereo-isomerism salt with chiral acid (such as (+)-tartrate, (-)-Pyrrolidonecarboxylic acid, (-)-two-toluoyl-L-tartaric acid, (+)-amygdalic acid, (-)-oxysuccinic acid and (-)-camphorsulfonic acid), be separated these diastereomers by preferential crystallization, and these salt that then dissociate are to provide the individual enantiomer of this free alkali.
Wherein compound of the present invention exists for two or more optical isomeric form, and a kind of enantiomer in a pair enantiomer can represent the advantage being better than another kind of enantiomer, such as, in biological activity.Therefore, in some cases, may it is desirable to the only one in a pair enantiomer, or the only one in multiple diastereomer is used as a kind of therapeutical agent.
Therefore, in another embodiment (embodiment 1.67), the invention provides the composition of a kind of compound comprised according to embodiment 1.66, these compositions have one or more chiral centre, and wherein at least 55% (such as at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of embodiment 1.65 is rendered as a kind of single optical isomer (such as enantiomorph or diastereomer).
In a generic embodiment (embodiment 1.68), 99% or more (such as substantially whole) of the total amount of the compound of embodiment 1.66 (or for compound) are rendered as a kind of single optical isomer.
Such as, in an embodiment (embodiment 1.69), this compound is rendered as a kind of single enantiomer.
In another embodiment (embodiment 1.70), this compound is rendered as a kind of single diastereomer.
Present invention also offers the mixture of multiple optical isomer, these optical isomers can be racemization or non-racemization.Therefore, the invention provides:
1.71 a kind of compounds according to embodiment 1.66, this compound is in the form of the racemic mixture of multiple optical isomer.
1.72 a kind of compounds according to embodiment 1.66, this compound is in the form of the non-racemic mixture of multiple optical isomer.
isotropic substance
Compound of the present invention as definition middle any one of embodiment 1.1 to 1.72 can comprise one or more isotopic, and mentions that a concrete element is included in all isotropic substances of this element within the scope of it.Such as, mention that hydrogen is included within the scope of it 1h, 2h (D) and 3h (T).Similarly, mention that carbon and oxygen are included within the scope of it respectively 12c, 13c and 14c and 16o and 18o.
In a similar fashion, mention that concrete functional group is also included within the isotopic variations within the scope of it, unless context indicates in addition.Such as, mention that an alkyl group (such as an ethyl group) also contains multiple variant, one or more hydrogen atoms wherein in this group are in the form of deuterium or tritium isotope, be such as that wherein all five hydrogen atoms are in the isotopic form of deuterium (a complete deuterated ethyl group) in an ethyl group.
These isotropic substances can be radioactive or inactive.In one embodiment of the present of invention (embodiment 1.73), the compound any one of embodiment 1.1 to 1.72 does not comprise radio isotope.This compounds is preferred for therepic use.But in another embodiment (embodiment 1.74), the compound any one of embodiment 1.1 to 1.72 can comprise one or more radio isotope.It can be useful for comprising this type of radioisotopic compound under diagnosis background.
solvate
The compound with chemical formula (1) as definition middle any one of embodiment 1.1 to 1.74 can form solvate.Preferred solvate is the solvate formed in the solid-state structure (such as crystalline structure) by the molecular juction of a kind of nontoxic pharmaceutically acceptable solvent (hereinafter referred to as solvation materialization solvent) being incorporated into compound of the present invention.The example of this kind solvent comprises water, alcohol (such as ethanol, Virahol and butanols) and dimethyl sulfoxide (DMSO).Solvate is by preparing compound recrystallization of the present invention with the mixture of a kind of solvent or the solvent that comprises this solvation materialization solvent.When any given whether formed a kind of solvate and determined by the analysis making the crystal of this compound and stand to use well-known and technology (such as thermogravimetric analysis (TGE), dsc (DSC) and X-ray crystallography) that is standard to carry out.These solvates can be stoichiometric or non-stoichiometric solvates.Particularly, preferred solvate is hydrate, and the example of hydrate comprises semihydrate, monohydrate and dihydrate.
Therefore, in other embodiment 1.75 and 1.76, the invention provides:
1.75 a kind of compounds according to any one of embodiment 1.1 to 1.74, this compound is in a kind of form of solvate.
1.76 a kind of compound according to embodiment 1.75, wherein this solvate is a kind of hydrate.
In order to discuss solvate in more detail and in order to manufacture and to characterize their method, see people such as cloth beautiful jades (Bryn), the solid state chemistry (Solid-State Chemistry of Drugs) of medicine, the second edition, is published by SSCI, western Lafayette company, IN, USA, 1999, ISBN 0-967-06710-3.
Alternately, compound of the present invention can be anhydrous, instead of exists for a kind of hydrate.Therefore, in another embodiment (embodiment 1.77), as defined any one of embodiment 1.1 to 1.74, the invention provides the compound that one is in anhydrous form (such as anhydrous crystalline forms).
crystallization and amorphous form
Compound any one of embodiment 1.1 to 1.77 can exist with crystallization or noncrystalline (such as amorphous) state.Whether a kind of compound easily can pass through standard technique (such as X-ray powder diffraction (XRPD)) with crystalline state existence is determined.Crystal and crystalline structure thereof can use multiple technologies (to comprise single crystal X-radiocrystallgraphy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and near infrared spectroscopy (such as using Fourier transform near infrared spectroscopy (FTIR)) to characterize.Under the humidity condition of change, the performance of these crystal is studied by the vapor sorption of specific gravity test and is also analyzed by XRPD.A kind of determination of crystalline structure of compound is undertaken by X-ray crystallography, X-ray crystallography can (such as described herein those and as at basic crystal theory (Fundamentals of Crystallography) according to conventional methods, C. Ji Aikewazuo (Giacovazzo), H.L. Monaco (Monaco), D. bit fertile (Viterbo), F. this is up to inner (Scordari), G. lucky (Gilli), G. Zha Nuodi (Zanotti) and the triumphant base of a fruit of M. (Catti), (crystallography League of Nations/Oxford University Press (International Union of Crystallography/Oxford University Press), 1992ISBN 0-19-855578-4 (p/b), 0-19-85579-2 (h/b)) described in) carry out.This technology comprises analysis and the explanation of the X-ray diffraction of single crystal.In amorphous solid, the three-dimensional structure normally existed in crystalline form does not exist, and these molecule positions being relative to each other in amorphous form are random substantially, see people's pharmaceutical science magazine (J.Pharm.Sci.) (1997) such as such as Chinese cocks (Hancock), 86,1.
Therefore, in a further embodiment, the invention provides:
1.78 a kind of compound according to any one of embodiment 1.1 to 1.77, this compound is in crystallized form.
1.79 a kind of compound according to any one of embodiment 1.1 to 1.77, this compound is:
A () is from 50% to 100% crystallization, and at least 50% crystallization more specifically, or at least 60% crystallization, or at least 70% crystallization, or at least 80% crystallization, or at least 90% crystallization, or at least 95% crystallization, or at least 98% crystallization, or at least 99% crystallization, or at least 99.5% crystallization, or at least 99.9% crystallization, such as 100% crystallization.
1.80 a kind of compound according to any one of embodiment 1.1 to 1.77, this compound is in amorphous form.
prodrug
As in any one of embodiment 1.1 to 1.74 the compound with chemical formula (1) that defines can present with the form of prodrug.Mean such as any following compound by " prodrug ", this compound is converted into the bioactive compound with chemical formula (1) in vivo, as in any one of embodiment 1.1 to 1.74 define.
Such as, some prodrugs are esters (ester unstable in acceptable metabolism on such as a kind of physiology) of this active compound.In metabolic process, this ester group (-C (=O) OR) is cleaved, to produce this active medicine.This type of ester is formed by the esterification of any oh group existed in such as parent compound, and time suitable, any other reactive group existed in this parent compound of priority protection, carries out protection if necessary subsequently.
In addition, some prodrugs are by enzyme activation, and to produce this active compound or a kind of following compound, this compound produces this active compound (such as, as in ADEPT, GDEPT, LIDEPT etc.) after further chemical reaction.Such as, this prodrug can be a kind of sugar derivatives or other glycoside conjugate, can be maybe a kind of amino acid ester derivative.
Therefore, in another embodiment (embodiment 1.81), the invention provides the prodrug of a kind of compound as definition middle any one of embodiment 1.1 to 1.74, wherein this compound comprises a functional group, and this functional group can be converted to form an oh group or amino group in physiological conditions.
complex compound and cage modle thing
Chemical formula (1) in embodiment 1.1 to 1.81 also includes the complex compound (such as clathrate complex or the clathrate compound with compound such as cyclodextrin, or with the complex compound of metal) of the compound of embodiment 1.1 to 1.81.
Therefore, in another embodiment (embodiment 1.82), the invention provides a kind of compound according to any one of embodiment 1.1 to 1.81, this compound is in the form of complex compound or cage modle thing.
biological activity and therepic use
Compound of the present invention has the activity as muscarinic M1 receptor stimulant.The muscarine activity of these compounds can use the mensuration of the phosphorylation-ERK1/2 described in following instance A to determine.
A significant advantage of compound of the present invention is that, relative to M2 and M3 receptor subtype, they have high selectivity for M1 acceptor.Compound of the present invention is not neither the agonist of M2 and M3 receptor subtype is again antagonist.Such as, in view of in the odor measurement described in example A, compound of the present invention typically has the pEC of at least 6 (preferably at least 6.5) for M1 acceptor 50value and be greater than the E of 80 (being preferably greater than 95) maxvalue, they are in the odor measurement of example A, can have when testing for M2 and M3 hypotype the pEC being less than 5 50value and be less than 20% E maxvalue.
Therefore, in embodiment 2.1 to 2.9, the invention provides:
2.1 a kind of compounds according to any one of embodiment 1.1 to 1.82, for using in medicine.
2.2 a kind of compound according to any one of embodiment 1.1 to 1.82, for being used as a kind of muscarinic M1 receptor stimulant.
2.3 a kind of compounds according to any one of embodiment 1.1 to 1.82, this compound is a kind of muscarinic M1 receptor stimulant, the mensuration of example A herein or substantially similar one measure in have from the pEC in 6.0 to 7.9 scopes for M1 acceptor 50the E of at least 90 max.
2.4 a kind of compounds according to embodiment 2.3, this compound a kind ofly has from the pEC in 6.5 to 7.5 scopes 50muscarinic M1 receptor stimulant.
2.5 a kind of compounds according to embodiment 2.3 or embodiment 2.4, this compound has the E of at least 95 for M1 acceptor max.
2.6 a kind of compounds according to any one of embodiment 2.3 to 2.5, as compared to muscarinic M2 with M3 acceptor, this compound has selectivity to M1 acceptor.
2.7 a kind of compounds according to any one of embodiment 2.3 to 2.6, this compound has for muscarinic M2 and M3 receptor subtype the pEC being less than 5 50with the E being less than 50 max.
2.8 a kind of compounds according to embodiment 2.7, this compound has for muscarinic M2 and M3 receptor subtype the pEC being less than 4.5 50and/or be less than the E of 30 max.
2.9 a kind of compounds according to any one of embodiment 1.1 to 1.82 and embodiment 2.3 to 2.8, for using in treatment is by the receptor-mediated disease of muscarinic M1 or the patient's condition.
By means of its muscarinic M1 receptor agonist activity, compound of the present invention can be used on treatment alzheimer's disease, schizophrenia and other psychotic disorders, cognitive disorder and other by the receptor-mediated disease of muscarinic M1, and can be used in treatment various types of pain in.
Therefore, in embodiment 2.10 to 2.26, the invention provides:
2.10 a kind of compound according to any one of embodiment 1.1 to 1.82, is used for the treatment of cognitive disorder or psychotic disorders.
2.11 according to embodiment 2.10 for a kind of compound, wherein this cognitive disorder or psychotic disorders comprise, result from a kind of patient's condition or associated being selected from the following: cognitive disorder, mild cognitive impairment, Frontotemporal dementia, vascular dementia, dementia with Lewy body, presenile dementia, senile dementia, Friedrich ataxia, mongolism, Huntington Chorea, hyperkinesis, manic, tourette's syndrome, alzheimer's disease, stein-leventhal syndrome, cognitive function (comprises attention, directed, learning disorder, memory (i.e. dysmnesia, lethe, lethe obstacle, transient Global Amnesia Syndrome and age-related memory damage) and linguistic function) damage, as the cognitive impairment of the result of apoplexy, Huntington's disease, Pick's disease, aids related dementia or other dull-witted state (such as multi-infarct dementias, alcoholic dementia, hypothyroidism (hypotiroidism) related dementias, and the dementia relevant to other degeneration obstacles (such as cerebellar atrophy and amyotrophic lateral sclerosis), other acute or subacute patient's condition such as delirium or depression (pseudodementia state) wound of cognitive decline, head trauma, Age-Related Cognitive Decline, apoplexy, nerve degeneration, drug-induced state, neurotoxicity agent may be caused, age-related cognitive damages, autism related cognitive impairments, mongolism, psychosis related cognitive defect, and related cognitive impairment after electro-shock therapy, (Nicotine is comprised owing to drug abuse or drug withdrawal, hemp, Amphetamine, Cocaine) cognitive disorder, hyperkinetic syndrome (ADHD) and dyskinesia (such as Parkinson's disease, the Parkinson of neuroleptic induction and tardive dyskinesia), schizophrenia, schizophreniform diseases, psychotic depression, mania, acute mania, bigoted, cause unreal and delusional disorder, personality disorder, obsession, Schizophreniform obstacle, delusional disorders, owing to malignant tumour, metabolic disturbance, the psychosis of endocrinopathy or narcolepsy, owing to the psychosis of drug abuse or drug withdrawal, bipolar disorder and schizophrenia-affective disorder.
2.12 a kind of compounds according to any one of embodiment 1.1 to 1.82, are used for the treatment of alzheimer's disease.
2.13 a kind of compounds according to any one of embodiment 1.1 to 1.82, are used for the treatment of schizophrenia.
2.14 treatment experimenter (the such as mammalian subject such as mankind, such as need the mankind that this type of is treated) a kind of method of cognitive disorder, this method comprises a kind of compound according to any one of embodiment 1.1 to 1.82 giving to treat effective dose.
2.15 a kind of methods according to embodiment 2.14, wherein this cognitive disorder comprise, result from as in embodiment 2.11 a kind of patient's condition or associated of defining.
2.16 a kind of methods according to embodiment 2.15, wherein this cognitive disorder results from alzheimer's disease or associated.
2.17 a kind of methods according to embodiment 2.16, wherein this cognitive disorder is schizophrenia.
2.18 are manufacturing according to the compound in embodiment 1.1 to 1.82 described in any one purposes be used for the treatment of in the medicine of cognitive disorder.
2.19 purposes according to embodiment 2.10, wherein this cognitive disorder comprise, result from as in embodiment 2.11 a kind of patient's condition or associated of defining.
2.20 purposes according to embodiment 2.19, wherein this cognitive disorder results from alzheimer's disease or associated.
2.21 purposes according to embodiment 2.19, wherein this cognitive disorder is schizophrenia.
2.22 a kind of compounds according to any one of embodiment 1.1 to 1.82, are used for the treatment of the following or alleviate its severity: acute, chronic, nervosa or inflammatory pain, sacroiliitis, migraine, cluster headache, trigeminal neuralgia, heretic, popularity neurodynia, visceral pain, osteo-arthritic pain, postherpetic neuralgia, diabetic neuropathy, radiculalgia, sciatica, backache, head or neck pain, serious or intractable pain, experiences nociceptive pain, explosive pain, postoperative pain, or cancer pain.
2.23 treat the followings or alleviate a kind of method of its severity: acute, chronic, nervosa, or inflammatory pain, sacroiliitis, migraine, cluster headache, trigeminal neuralgia, heretic, popularity neurodynia, visceral pain, osteo-arthritic pain, postherpetic neuralgia, diabetic neuropathy, radiculalgia, sciatica, backache, head or neck pain, serious or intractable pain, experience nociceptive pain, explosive pain, postoperative pain, or cancer pain, this method comprises a kind of compound according to any one of embodiment 1.1 to 1.82 giving to treat effective dose.
2.24 a kind of compounds according to any one of embodiment 1.1 to 1.82, are used for the treatment of periphery obstacle (such as reducing the intraocular pressure in glaucoma) and treatment xerophthalmia and xerostomia (comprising Sjogren syndrome).
A kind of method of 2.25 treatment periphery obstacles (such as reducing the intraocular pressure in glaucoma) and treatment xerophthalmia and xerostomia (comprising Sjogren syndrome), this method comprises a kind of compound according to any one of embodiment 1.1 to 1.82 giving to treat effective dose.
2.26 a kind of compounds according to any one of embodiment 1.1 to 1.82 are for the manufacture of the purposes of following medicine, this medicine is used for the treatment of the following or alleviates its severity: acute, chronic, nervosa, or inflammatory pain, sacroiliitis, migraine, cluster headache, trigeminal neuralgia, heretic, popularity neurodynia, visceral pain, osteo-arthritic pain, postherpetic neuralgia, diabetic neuropathy, radiculalgia, sciatica, backache, head or neck pain, serious or intractable pain, experience nociceptive pain, explosive pain, postoperative pain, or cancer pain, or be used for the treatment of periphery obstacle (such as reducing the intraocular pressure in glaucoma) and treat xerophthalmia and xerostomia (comprising Sjogren syndrome).
2.27 are used for the treatment of according to the compound in embodiment 1.1 to 1.82 described in any one purposes such as sending out the skin lesion of the blister patient's condition owing to pemphigus vulgaris, dermatitis herpetiformis, pemphigoid and other skin.
2.28 a kind of compounds according to any one of embodiment 1.1 to 1.82 are used for the treatment of, prevent, improve or reverse the patient's condition relevant with mobility to the gastrointestinal function changed, such as functional dyspepsia, irritable bowel syndrome, the refluence of stomach oesophagus hydrochloric acid in gastric juice (GER) and esophageal peristalsis obstacle, the purposes of the symptom of gastroparesis and chronic diarrhoea.
2.29 are used for the treatment of olfactory disorder such as Bo Sima-Heng Jin-Kristiansen syndrome (Bosma-Henkin-Christiansen syndrome), chemical poisoning (such as selenium and silver), hypopituitarism, kallman syndrome, fracture of skull, oncotherapy and hypothyroid purposes according to the compound in embodiment 1.1 to 1.82 described in any one.
for the preparation of the method for compound with chemical formula (1)
What the compound with chemical formula (1) can be known according to those of ordinary skill in the art is prepared with synthetic method as described here.
Therefore, in another embodiment (embodiment 3.1), the invention provides for the preparation of any one of embodiment 1.1 to 1.82 a kind of technique of compound that defines, this technique comprises:
(A) a kind of compound with chemical formula (10) is made
Wherein R 3, R 4, R 5, X 1and X 2as in any one of embodiment 1.1 to 1.82 define, and there is chemical formula R 1r 2a kind of compound of NH reacts under amide forming conditions; Or
(B) a kind of compound with chemical formula (11) is made:
With (i), there is chemical formula Cl-C (=O)-CH 2-R 4a kind of compound react under a kind of existence of alkali; Or (ii) with there is chemical formula R 4-CH 2a kind of compound of-OH and triphosgene react; Or (iii) and 4-nitrophenyl chlorocarbonate, subsequently with there is chemical formula R 4-CH 2a kind of compound of-OH reacts under a kind of existence of alkali;
And optionally:
(C) converting compounds one with chemical formula (1) is the compound that another kind has chemical formula (1).
In process variants (A), this reaction can be used to form amido linkage a type reagent existence under carry out.The example of this type of reagent comprises 1, 3-dicyclohexyl carbodiimide (the DCC) (people such as Skien (Sheehan), JACS (J.Amer.Chem Soc.) 1955, 77, 1067), 1-ethyl-3-(3 '-dimethylaminopropyl)-carbodiimide (herein also referred to as EDC or EDAC) (people such as Skien (Sheehan), organic chemistry magazine (J.Org.Chem.), 1961, 26, 2525), based on the coupling agent of urea as O-(7-azepine benzo triazol-1-yl)-N, N, N ', the coupling agent of N '-tetramethyl-urea hexafluorophosphate (HATU) and Ji Yu Phosphonium is as 1-benzo-triazolyl oxygen base three-(pyrrolidyl) Phosphonium hexafluorophosphate (PyBOP) (people such as Karstlo (Castro), Tet Lett (Tetrahedron Letters), 1990, 31, 205).Coupling agent based on carbodiimide advantageously combinationally uses with 1-hydroxyl-7-azepine benzotriazole (HOAt) (L.A. Carpino (Carpino), JACS, 1993, 115, 4397) or I-hydroxybenzotriazole (HOBt) (people such as Kang Nige (Konig), German chemical journal (Chem.Ber.), 103,708,2024-2034).A kind of preferred am amide coupling agent is HATU.
Linked reaction typically in non-aqueous aprotic solvent such as acetonitrile, diox, methyl-sulphoxide, methylene dichloride, dimethyl formamide or N-Methyl pyrrolidone, or optionally miscible with one or more common-solvent together with aqueous solvent in carry out.This reaction can at room temperature be carried out, or carries out under having less reactive situation at the temperature of reactant such as up to about 100 DEG C (such as 50 DEG C-80 DEG C) at the temperature raised suitably wherein.This reaction is optionally carried out under the existence of a kind of non-interfering alkali such as a kind of tertiary amine (such as triethylamine or DIPEA).
As an alternative, a kind of reactive derivatives of this carboxylic acid can be used, such as acid anhydrides or acyl chlorides.Under the existence of a kind of alkali such as sodium bicarbonate, this acyl chlorides typically with there is chemical formula R 1r 2the compound of NH reacts.This acyl chlorides can use the method for standard, such as, by being carried out processing preparing by this acid oxalyl chloride under the existence of the dimethyl formamide of catalytic amount.
Process variants (B) typically carries out under the existence of a kind of non-interfering alkali such as triethylamine in the sprotic solvent of one such as methylene dichloride or ethylene dichloride.This reaction can at room temperature be carried out.
The midbody compound with chemical formula (10) is prepared by the serial reaction shown in following scheme 1.
In reaction scheme 1, under reduction amination condition, piperidine ester (12, R "=ethyl or methyl) reacts with the ketone (13) replaced.This reductive amination process is typically along with mild heat (such as extremely from the temperature of about 40 DEG C to about 70 DEG C), under the existence that sodium cyanoborohydride and zinc chloride combine or sodium triacetoxy borohydride and titanium isopropoxide combine, carry out in a kind of the solvent such as methylene dichloride or ethylene dichloride that comprise acetic acid, to provide a kind of intermediate ester compound (14), then lithium hydroxide or sodium hydroxide is used optionally to be hydrolyzed, to provide compound (10) this intermediate ester compound in a mild condition.
The compound with chemical formula (11) is prepared by the reaction sequence shown in following scheme 2.
In scheme 2, under the reduction amination condition of the above-mentioned type, piperidine ester (12; R "=ethyl or methyl) react with ketone (15), to provide a kind of intermediate ester (not shown), then lithium hydroxide is used optionally to be hydrolyzed, to provide carboxylic acid (16).Then carboxylic acid (16) and a kind of amine HNR 1r 2react under amide forming conditions (see more than); to provide a kind of midbody acid amide compound (not shown); then protection is gone, to provide compound (11) by removing Boc group with acid (such as trifluoroacetic acid is in methylene dichloride) process.
The compound with chemical formula (10) is also prepared by the reaction sequence shown in following scheme 3.
In scheme 3, be used in the sodium borohydride in methyl alcohol, the ketone (13) of replacement is reduced to alcohol (17).Then under the existence of a kind of tertiary amine such as triethylamine or DIPEA, use corresponding SULPHURYL CHLORIDE in methylene dichloride, alcohol (17) is sulphonate (18, R=methyl, trifluoromethyl or 4-aminomethyl phenyl) by activation.In nucleophilic substitution reaction, sulphonate (18) and piperidine ester (12; R "=ethyl or methyl) react, this reaction is typically along with mild heat (such as extremely from the temperature of about 40 DEG C to about 70 DEG C), neat, solvent-free, or carry out in a kind of applicable solvent such as tetrahydrofuran (THF), acetonitrile or N,N-DIMETHYLACETAMIDE, to provide compound (14), then lithium hydroxide or sodium hydroxide is used optionally to be hydrolyzed in a mild condition, to provide compound (10).
Once be formed, the method known by those of ordinary skill in the art, one has the compound of chemical formula (1) or its a kind of shielded derivative can be converted into the compound that another kind has chemical formula (1).At received text such as Advanced Organic Chemistry (Advanced Organic Chemistry and organic synthesis (Organic Syntheses) (reference see following) or Fei Saiershi (Fieser's) organic synthesis reagent (Fiesers ' Reagents for Organic Synthesis) for the example that is the synthesis step of another functional group by a functional group conversions, 1-17 rolls up, John Wiley Publishing Company (John Wiley), edited in (ISBN:0-471-58283-2) by Mary Fei Saier (Mary Fieser) and propose.
In above-mentioned many reactions, may be necessary that the one or more group of protection occurs to prevent from reacting position undesirable on this molecule.The example of blocking group and for the protection of with go to protect functional group method can blocking group (Protective Groups in Organic Synthesis) in organic synthesis (T. Green (Greene) and P. 5 hereby (Wuts); 3rd edition; John Willie father and son, 1999) find in.
In the multiple method that the compound manufactured by preceding method is known by those of ordinary skill in the art, any one carrys out abstraction and purification, and the example of these class methods comprises recrystallization and chromatographic technique, such as column chromatography (such as flash chromatography) and HPLC.
medicament preparation
Although active compound likely gives separately, preferably it is presented with pharmaceutical composition (such as preparation) form.
Therefore, in an alternative embodiment of the invention (embodiment 4.1), provide a kind of pharmaceutical composition, this pharmaceutical composition comprise at least one any one of embodiment 1.1 to 1.82 in the compound with chemical formula (1) that defines together with the pharmaceutically acceptable vehicle of at least one.
In an embodiment (embodiment 4.2), said composition is tablet composition.
In another embodiment (embodiment 4.3), said composition is capsule composition.
These one or more pharmaceutically acceptable vehicle can be selected from, such as, and carrier (such as solid-state, liquid or semi-solid state carrier), adjuvant, thinner (such as solid diluent, such as weighting agent or swelling agent; And liquid diluent, such as solvent and cosolvent), granulating agent, binding agent, flow promotor, Drug coating, Controlled release formulation (such as postponing or delayed release polymer or wax), bonding agent, disintegrating agent, buffer reagent, lubricant, sanitas, antimycotic and antibacterial agent, antioxidant, buffer reagent, tension regulator, thickening material, seasonings, sweeting agent, pigment, softening agent, odor mask, stablizer or conventional any other vehicle being used for pharmaceutical composition.
As term used herein " pharmaceutically acceptable " means following compound, material, composition and/or formulation, it is within the scope of correct medical judgment, be suitable for the tissue of contact experimenter (such as human experimenter) and there is no excessive toxicity, pungency, anaphylaxis or other problems or complication, matching with rational benefit/risk ratio.Often kind of vehicle must be " acceptable " in the meaning that other compositions with this preparation are compatible.
The pharmaceutical composition comprising the compound with chemical formula (1) can be prepared according to known technology, see such as, the pharmaceutical science of Lei Mingdun (Remington ' s Pharmaceutical Sciences), Mike publishing company (Mack Publishing Company), Easton (Easton), PA, USA.
These pharmaceutical compositions can be in be suitable for oral, parenteral, local, in nose, any form of intrabronchial, sublingual, eye, ear, rectum, intravaginal or administration through skin.
The pharmaceutical dosage form being suitable for oral administration comprises tablet (dressing or non-dressing), capsule (hard or soft shell), caplet, pill, lozenge, syrup, solution, powder, particle, elixir and suspension, sublingual tablet, wafer or patch such as buccal bioadhesive tablet.
The active compound that tablet composition can comprise a unitary dose together with a kind of inert diluent or carrier such as, as a kind of sugar or sugar alcohol, lactose, sucrose, Sorbitol Powder or N.F,USP MANNITOL; And/or the thinner that a kind of non-saccharide is derivative, as sodium carbonate, calcium phosphate, calcium carbonate, or a Mierocrystalline cellulose or derivatives thereof, such as Microcrystalline Cellulose (MCC), methylcellulose gum, ethyl cellulose, Vltra tears and starch (as W-Gum).Tablet can also comprise such standard analysis, as bonding agent and granulating agent (as polyvinylpyrrolidone), disintegrating agent (such as expandable crosslinked polymkeric substance, the carboxymethyl cellulose as crosslinked), lubricant (such as stearate), sanitas (such as p-Hydroxybenzoate), antioxidant (such as BHT), buffer reagent (damping fluid of such as phosphoric acid salt or Citrate trianion) and effervescent (such as the mixture of Citrate trianion/supercarbonate).This type of vehicle is well-known, and does not need here to discuss in detail.
Can design tablet with when contacting with gastric juice (immediately release tablet) discharge this medicine or (Co ntrolled release tablet) time period or contact with GI specific region through extending discharges in a controlled manner.
These pharmaceutical compositions typically comprise the combination from general 1% (w/w) to the activeconstituents of general 95%, preferred % (w/w) and the pharmaceutically acceptable vehicle of one (such as defined above) from 99% (w/w) to 5% (w/w) or this type of vehicle.Preferably, these compositions comprise activeconstituents from general 20% (w/w) to general 90% (w/w) and from a kind of vehicle pharmaceutically of 80% (w/w) to 10% or the combination of multiple vehicle.These pharmaceutical compositions comprise from general 1% to general 95%, preferably from the activeconstituents of general 20% to general 90%.Pharmaceutical composition according to the present invention is passable, such as, is in following unit dosage, as being in the form of ampulla, bottle agent, suppository, precharging type syringe agent, drageeing, pulvis, tablet or capsule.
Tablet and Capsula can comprise, such as, and 0-20% disintegrating agent, 0-5% lubricant, 0-5% glidant and/or 0-99% (w/w) weighting agent/or swelling agent (depending on drug dose).They also can comprise 0-10% (w/w) polymer binder, 0-5% (w/w) antioxidant, 0-5% (w/w) pigment.In addition, slow releasing tablet typically comprises 0-99% (w/w) Co ntrolled release (such as delaying release) polymkeric substance (depending on dosage).The film-coat of this tablet or capsule typically comprises 0-10% (w/w) polymkeric substance, 0-3% (w/w) pigment and/or 0-2% (w/w) softening agent.
Parenteral formulations typically comprises 0-20% (w/w) damping fluid, 0-50% (w/w) cosolvent and/or 0-99% (w/w) water for injection (WFI) (depending on the situation of dosage and whether freeze-drying).The preparation accumulated for intramuscular also can comprise 0-99% (w/w) oil.
These medicament preparations may present to patient with " the patient's bag " that comprise the whole course for the treatment of being in individual packaging (normally Blister Package).
The compound with chemical formula (1) will be present in unit dosage at large, and will typically comprise enough compounds to provide the biological activity of a desired level after this manner.Such as, a kind of preparation can comprise the activeconstituents from 1 nanogram to 2 gram, such as, from the activeconstituents of 1 nanogram to 2 milligram.Within the scope of these, the concrete sub-scope of compound is that (more common is from 10 milligrams to 1 gram for the activeconstituents of 0.1 milligram to 2 grams, such as 50 milligrams to 500 milligrams) or 1 microgram to 20 milligram (such as 1 microgram to 10 milligram, the such as activeconstituents of 0.1 milligram to 2 milligrams).
For oral compositions, a unit dosage can comprise from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, such as 50 milligrams to 1 gram, the such as active compound of 100 milligrams to 1 gram.
This active compound will need its patient, the such as mankind or animal patient with the amount (significant quantity) enough reaching desired result for the treatment of.The precise volume of the compound given can be determined according to standard program by supervision doctor.
example
The present invention illustrates referring now to the specific embodiment described in following instance, but does not limit.
embodiment 1-32
Prepare the compound of the example 1 to 32 shown in following table 1.Set forth in table 3 they NMR and LCMS characteristic and in order to prepare their method.The parent material for each example is listed in table 2.
table 1
general method
When do not comprise prepare approach, relevant intermediate is commercially available.Commercial reagents is utilized without being further purified.Room temperature (rt) refers to general 20 DEG C-27 DEG C.At 400MHz record on Brooker that (Bruker) or NEC optical laboratory (Jeol) instrument 1h NMR composes.Chemical shift value is represented with PPM (ppm) (i.e. (δ)-value).Following abbreviation is used: s=is unimodal, br=broad peak, d=doublet, t=triplet, q=quartet, quint=quintet, td=tri-doublet, tt=tri-triplet, qd=tetra-doublet, ddd=doublet, ddt=triplet, m=multiplet in pairs in pairs for multiple NMR signal.Coupling constant is listed in J value, measures with Hz.Correction NMR and mass spectrometry results are to take into account background peaks.Chromatography refers to and uses 60-120 order silica gel to carry out and the column chromatography come into force under nitrogen pressure (flash chromatography) condition.TLC for monitoring reaction refer to use specific moving phase and from Merck & Co., Inc. (Merck) silica gel F254 as stationary phase run TLC.The reaction of microwave mediation is finding to carry out in microwave reactor than safe smelting (Biotage) starter of Austria or CEM.
Use the electrospray condition as specified for often kind of compound in Detailed Experimental part, Shimadzu (Shimadzu) LC-2010EV, this (Waters) ZQ-2000, UPLC-Mass SQD-3100 of water or applying biological system (Applied Biosystem) API-2000 spectrum analyzer carry out mass spectroscopy.
Typically be prepared type HPLC (gill pine semi-preparative (Gilson Semi-Prep) HPLC) under the following conditions: post: Féraud door (Phenomenex) Gemini NX 5 μm of C18 110A Axia (100x 30mm); Moving phase: solvent orange 2 A: MeCN; Solvent B: comprise water-based NH 3and 0.1 of 5%MeCN or 0.2% water of solution (28%); Gradient: the solvent orange 2 A of 20% to 60% is through 14.4min in solvent B, keep 60% solvent orange 2 A to continue 1.6min in solvent B, 100% solvent orange 2 A continues 1.6min, flow velocity: 30mL/min; Determined wavelength: 210nm.
Typically using the electrospray condition as specified for often kind of compound, carrying out LCMS experiment under the following conditions:
Method A and B
Instrument: this Alliance 2795 of water, this 2996PDA detector of water, Micromass ZQ; Post: this X-bridge of water C-18,2.5 microns, 2.1x 20mm or Féraud door Gemini-NX C-18,3 microns, 2.0x 30mm; Gradient [time (min)/in C solvent D (%)]: method A:0.00/2,0.10/2,2.50/95,3.50/95,3.55/2,4.00/2 or method B:0.00/2,0.10/2,8.40/95,9.40/95,9.50/2,10.00/2; Solvent: solvent C=2.5L H 2o+2.5mL ammonia solution; Solvent D=2.5L MeCN+135mL H 2o+2.5mL ammonia solution); Volume injected 3uL; UV detects 230 to 400nM; Column temperature 45 DEG C; Flow velocity 1.5mL/min.
Method C
Instrument: HP1100, HP DAD G1315A detector, Micromass ZQ; Post: Féraud door Gemini-NX C-18,3 microns, 2.0x 30mm; Gradient [time (min)/in C solvent D (%)]: method C:0.00/2,0.10/2,8.40/95,9.40/95,9.50/2,10.00/2; Solvent: solvent C=2.5L H 2o+2.5mL ammonia solution; Solvent D=2.5L MeCN+135mL H 2o+2.5mL ammonia solution); Volume injected 3uL; UV detects 230 to 400nM; Column temperature 45 DEG C; Flow velocity 1.5mL/min.
Method D
Instrument: this Alliance 2795 of water, this 2996PDA detector of water, Micromass ZQ; Post: this X-bridge of water C-18,2.5 microns, 2.1x 20 μm, flow velocity 1.0mL/min; Volume injected 5 μ L; 5%-95% acetonitrile: water+0.1% ammonium hydroxide.
Method E
Instrument: water this 2695Alliance, Micromass ZQ, 2996PDA and Varian (Varian) 385-LC ELSD, post: X bridge C18 3x 100mm x 3.5 μm, flow velocity 1mL/min; Volume injected 20 μ L, 5%-95% acetonitrile: water+2% formic acid
Run GC experiment under the following conditions:
Method F
Instrument: Agilent (Agilent) 6890, CP selects 624 posts; Inject 200 DEG C, 10psi H 2; Detect 250 DEG C, 25mL/min H 2, 400mL/min air; 8 DEG C, 35 DEG C, baking oven (2min)/min to 130 DEG C (4.1min)
Method G
Instrument: Agilent (Agilent) 6890, CP selects 624 posts; Inject 200 DEG C, 10psi H 2; Detect 250 DEG C, 25mL/min H 2, 400mL/min air; 4 DEG C, 35 DEG C, baking oven (2min)/min to 130 DEG C (5.75min)
The GC data in experimental section are provided: working time, retention time, per-cent peak area with following format.
Abbreviation
D=sky
DCM=methylene dichloride
DIPEA=diisopropylethylamine
DMF=dimethyl formamide
DMSO=methyl-sulphoxide
ES=electrospray ionisation effect
EtOAc=ethyl acetate
H=hour
HPLC=high performance liquid chromatography
LC=liquid chromatography
MeCN=acetonitrile
MeOH=methyl alcohol
Min=minute
MS=mass spectroscopy
NMR=nucleus magnetic resonance
Rt=room temperature
Sat.=saturated
Sol.=solution
STAB=sodium triacetoxy borohydride
THF=tetrahydrofuran (THF)
TLC=thin-layer chromatography
Prefix n-, s-, i-, t-and tert-have its common meaning: just, secondary, different, Yi Jishu.General synthesis program:
approach a
As by example 1 isomer 1; ethyl 3-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl } preparation of-8-azabicyclo [3.2.1] octane-8-carboxylicesters is illustrative, for being prepared the exemplary program of acid amides by STAB reduction amination and HATU coupling
At room temperature, by ethyl piperidine-4-carboxylicesters (0.797g, 0.78mL, 5.07mmol) with N-ethoxy carbonyl notropinon (1.00g, 5.07mmol) be dissolved in DCM (30mL), and add titanium isopropoxide (1.59g, 1.7mL, 5.58mmol).This reaction mixture is at room temperature stirred 1.5h.Add STAB (2.15g, 10.14mmol) and acetic acid (0.2mL), and by this reaction mixture at room temperature under a nitrogen stirring spend the night.By this reaction mixture by adding water (4mL) cancellation, and with DCM dilution, then filtered by Celite pad.This filtrate is used saturated NaHCO 3solution, saturated NaCl solution are washed, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 50g, 40-63 μm difficult to understand, 50mL/min, gradient 2% to 4.5%MeOH is in DCM]), to provide ethyl 3-[4-(ethoxy carbonyl) piperidin-1-yl]-8-azabicyclo [3.2.1] octane-8-carboxylicesters, be the separable mixture of multiple isomer.Isomer 1 (0.549g, 32%) in pale yellowish oil and the isomer 2 (0.137g, 8%) in pale yellowish oil.
LCMS (method A): isomer 1m/z 339 (M+H) +(ES +), at 1.78min, without UV activity.
LCMS (method A): isomer 2m/z 339 (M+H) +(ES +), at 1.68min, without UV activity.
At room temperature, by ethyl 3-[4-(ethoxy carbonyl) piperidin-1-yl]-8-azabicyclo [3.2.1] octane-8-carboxylicesters (0.549g, isomer 1 1.62mmol) is dissolved in THF (10mL), and adds 1M LiOH solution (1.62mL).This reaction mixture is at room temperature stirred 2 days.PH is carefully adjusted to pH 6 by adding concentrated hydrochloric acid, these solvents are removed under vacuo, to provide 1-[8-(ethoxy carbonyl)-8-azabicyclo [3.2.1] oct-3-yl] piperidines-4-carboxylic acid (0.50g, 100%) in pale solid shape.
LCMS (method A): m/z 311 (M+H) +(ES +), at 0.1min, without UV activity
By 1-[8-(ethoxy carbonyl)-8-azabicyclo [3.2.1] oct-3-yl] piperidines-4-carboxylic acid (0.50g, assuming that 1.62mmol) be dissolved in DMF (8mL), and add (1-methyl-cyclobutyl) amine hydrochlorate (0.295g, 2.44mmol), HATU (0.926g, 2.44mmol) with DIPEA (1.05g, 1.41mL, 8.12mmol).This reaction mixture is at room temperature stirred 60h and these solvents are removed under vacuo.By this resistates at DCM and saturated NaHCO 3distribute between solution, and this organic layer is washed by saturated NaCl solution and passes the post that is separated.The solvent of this organic filtrate is removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 25g, 40-63 μm difficult to understand, 25mL/min; gradient 0% to 10%MeOH is in DCM]); to provide ethyl 3-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl in light yellow gum }-8-azabicyclo [3.2.1] octane-8-carboxylicesters isomer 1 (0.208g, 34%).
Data in table 3
approach b
As by example 5 isomer 1, ethyl 3-{4-methoxyl group-4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl } preparation of-8-azabicyclo [3.2.1] octane-8-carboxylicesters is illustrative, for passing through NaCNBH 3the exemplary program of acid amides is prepared in reduction amination and HATU coupling
4-methoxy piperide-4-carboxylic acid methyl ester hydrochloride (0.500g, 2.38mmol) is dissolved in methyl alcohol (2mL), and with the K in minimal amount of water 2cO 3(0.329g, 2.38mmol) process is with desalination.This mixture is concentrated under vacuo, and with methylbenzene azeotropic to dry.This resistates and N-ethoxy carbonyl notropinon (0.470g, 2.39mmol) are dissolved in methyl alcohol (20mL), and add zinc chloride (0.975g, 7.15mmol).This reaction mixture is stirred 2h at 50 DEG C under nitrogen atmosphere, is then cooled to room temperature.Add NaCNBH 3(0.299g, 4.77mmol), and this reaction mixture is spent the night 50 DEG C of stirrings under a nitrogen.This reaction mixture is cooled to room temperature, and these solvents are removed under vacuo, this resistates DCM is diluted, and uses saturated NaHCO 3solution-treated, is filtered obtained multiphase mixture by Celite pad, and this filtrate is used saturated NaHCO 3solution, saturated NaCl solution are washed, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 25g, 40-63 μm difficult to understand, 50mL/min, gradient 0% to 10%MeOH is in DCM]), to provide ethyl 3-[4-methoxyl group-4-(methoxycarbonyl) piperidin-1-yl]-8-azabicyclo [3.2.1] octane-8-carboxylicesters, it is the separable mixture of multiple isomer.Isomer 1 (0.097g, 12%) in faint yellow oily and the isomer 2 (0.022g, 2.5%) in faint yellow oily.
LCMS (method A): isomer 1m/z 355 (M+H) +(ES +), at 1.47-1.50min, without UV activity.
LCMS (method A): isomer 2m/z 355 (M+H) +(ES +), at 1.47min, without UV activity.
At room temperature, by ethyl 3-[4-methoxyl group-4-(methoxycarbonyl) piperidin-1-yl]-8-azabicyclo [3.2.1] octane-8-carboxylicesters (0.097g, isomer 1 0.27mmol) is dissolved in THF (5mL), and adds 1M LiOH solution (0.3mL).This reaction mixture is at room temperature stirred 7 days.PH is carefully adjusted to pH 6 by adding concentrated hydrochloric acid, these solvents are removed under vacuo, to provide 1-[8-(ethoxy carbonyl)-8-azabicyclo [3.2.1] the oct-3-yl]-4-methoxy piperide-4-carboxylic acid (0.093g, 100%) in pale solid shape.
LCMS (method A): m/z 341 (M+H) +(ES +), at 0.83min, without UV activity.
By 1-[8-(ethoxy carbonyl)-8-azabicyclo [3.2.1] oct-3-yl]-4-methoxy piperide-4-carboxylic acid (0.093g, assuming that 0.27mmol) be dissolved in DMF (5mL), and add (1-methyl-cyclobutyl) amine hydrochlorate (0.05g, 0.411mmol), HATU (0.156g, 0.41mmol) with DIPEA (0.177g, 0.24mL, 1.37mmol).This reaction mixture is at room temperature stirred 60h and these solvents are removed under vacuo.By this resistates at DCM and saturated NaHCO 3distribute between solution, and the saturated NaCl solution of this organic layer is washed, and dry (MgSO 4).These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 10g, 40-63 μm difficult to understand, 25mL/min; gradient 0% to 10%MeOH is in DCM]); to provide ethyl 3-{4-methoxyl group-4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl in faint yellow glue }-8-azabicyclo [3.2.1] octane-8-carboxylicesters isomer 1 (0.028g, 25%).
Data in table 3
approach c
As by example 9, ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl } preparation of-6-azaspiro [3.4] octane-6-carboxylic ester is illustrative, for being prepared the exemplary program of carbamate by chlorocarbonate coupling
At room temperature, by ethyl piperidine-4-carboxylicesters (0.35g, 0.32mL, 2.22mmol) and 6-azaspiro [3.4] octane-6-carboxylic acid, 2-oxo-, 1,1-dimethyl ethyl ester (0.500g, 2.22mmol) is dissolved in DCM (20mL), and adds titanium isopropoxide (4.12g, 4.40mL, 14.5mmol).This reaction mixture is at room temperature stirred 1h.Add STAB (0.694g, 0.72mL, 2.44mmol) and acetic acid (0.05mL), and by this reaction mixture at room temperature under a nitrogen stirring spend the night.By this reaction mixture by adding saturated NaHCO 3solution (5mL) cancellation and stir 5 minutes.This reaction mixture DCM is carried out diluting and being filtered by Celite pad.This filtrate is separated and washs by saturated NaCl solution, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 50g, 40-63 μm difficult to understand, 50mL/min, gradient 0% to 5%MeOH is in DCM]), to provide tertiary butyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.739g, 90.9%) in faint yellow oily.
LCMS (method A): m/z 367 (M+H) +(ES +), at 1.94/1.99min, without UV activity
At room temperature, by tertiary butyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.739g, 2.02mmol) be dissolved in THF (10mL), and add 1M LiOH solution (2.02mL).This reaction mixture is at room temperature stirred and spends the night.This reaction mixture is adjusted to pH 5 by adding 1M HCl solution, and solvent is removed under vacuo, to provide 1-[pungent-2-base of 6-(tert-butoxycarbonyl)-6-azaspiro [3.4]] piperidines-4-carboxylic acid, it is not processed in the reaction be used in subsequently.
LCMS (method A): m/z 339 (M+H) +(ES +), at 0.12min, without UV activity
By 1-[pungent-2-base of 6-(tert-butoxycarbonyl)-6-azaspiro [3.4]] piperidines-4-carboxylic acid in DMF (5mL), and add (1-methyl-cyclobutyl) amine hydrochlorate (0.37g, 3.03mmol), HATU (0.844g, 2.22mmol) with DIPEA (1.305g, 10.1mmol).By this reaction mixture under a nitrogen in stirred overnight at room temperature.These solvents are removed under vacuo, and by this resistates at DCM and saturated NaHCO 3distribute between solution, the saturated NaCl solution of organic layer is washed, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 50g, 40-63 μm difficult to understand, 50mL/min; gradient 0% to 10%MeOH is in DCM]); to provide tertiary butyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl in white foam }-6-azaspiro [3.4] octane-6-carboxylic ester (0.627g, 76.7%).
LCMS (method A): m/z 406 (M+H) +(ES +), at 1.81min, without UV activity
By tertiary butyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester (0.627g; 1.55mmol) be dissolved in DCM (8mL), and add TFA (2mL).By this reaction mixture under a nitrogen in stirred overnight at room temperature, then these solvents are removed under vacuo, to provide 1-(pungent-2-base of 6-azaspiro [3.4])-N-(1-methyl-cyclobutyl) piperidines-4-carboxylic acid amides trifluoroacetic acid in deep yellow oily, it is directly used without being further purified.This resistates is dissolved in DCM (10mL), and adds NEt 3(0.49g, 0.65mL, 4.64mmol) and Vinyl chloroformate (0.25mg, 0.18mL, 0.57mmol), and by this reaction mixture under a nitrogen in stirred overnight at room temperature.These solvents are removed under vacuo, and by this resistates at DCM and saturated NaHCO 3distribute between solution, the saturated NaCl solution of organic layer is washed, and through MgSO 4dry.By this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 10g, 40-63 μm difficult to understand, 12mL/min; gradient 0% to 10%MeOH is in DCM]); to provide ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl in yellow colloidal }-6-azaspiro [3.4] octane-6-carboxylic ester (0.04g; 13%), be the mixture of diastereomer.
Data in table 3
approach d
As by example 9 isomer 2; ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl } preparation of-6-azaspiro [3.4] octane-6-carboxylic ester is illustrative; for the preparation of single diastereomer, carry out the exemplary program of chlorocarbonate coupling subsequently
By 6-azaspiro [3.4] octane-6-carboxylic acid, 2-oxo-, 1, 1-dimethyl ethyl ester (3.00g, 13.33mmol) be reduced to this alcohol, react under Mesylation condition, and by obtained diastereomer according to the information separated described in detail in patent WO 2010/089510, to produce tertiary butyl 2-[(methyl sulphonyl) oxygen base]-6-azaspiro [3.4] the octane-6-carboxylic ester isomer 1 (1.79g in white crystalline solid, 44% through two steps) and in the isomer 2 (0.965g of white crystalline solid, 24% through two steps).
LCMS (method B): isomer 1; M/z 306 (M+H) +(ES +), at 3.36min, without UV activity
LCMS (method B): isomer 2; M/z 306 (M+H) +(ES +), at 3.39min, without UV activity
Tertiary butyl 2-[(methyl sulphonyl) oxygen base]-6-azaspiro [3.4] octane-6-carboxylic ester isomer 1 (1.79g; 5.73mmol) be heated to 65 DEG C together with iso ethyl nicotinate (4.49g, 28.62mmol) and continue 5 days.This reaction mixture is reduced volume under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 100g, 40-63 μm difficult to understand, 50mL/min, gradient 1% to 4.5%MeOH is in DCM]), to provide tertiary butyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.264g, 12.5%) in yellow oily.
LCMS (method A): m/z 367 (M+H) +(ES +), at 1.97min, without UV activity.
By tertiary butyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.080g, 0.22mmol) at room temperature stir in DCM (10mL), and process with 4M HCl/ diox (1mL).This reaction mixture is at room temperature stirred and spends the night.This reaction mixture is concentrated in a vacuum, to provide a kind of yellow solid, by it without being further purified direct use.This resistates is dissolved in DCM (10mL), and adds NEt 3(0.066g, 0.1mL, 0.66mmol) and Vinyl chloroformate (0.036g, 0.03mL, 0.32mmol), and by this reaction mixture under a nitrogen in stirred overnight at room temperature.These solvents are removed under vacuo, and by this resistates at DCM and saturated NaHCO 3distribute between solution, the saturated NaCl solution of organic layer is washed, and through MgSO 4dry.By this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 10g, 40-63 μm difficult to understand, 12mL/min, gradient 0% to 8%MeOH is in DCM]), to provide ethyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.069g, 93%) in amber oily.
LCMS (method A): m/z 339 (M+H) +(ES +), at 1.71min, without UV activity.
At room temperature, by ethyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.069g, 0.20mmol) be dissolved in THF (4mL), and add 1M LiOH solution (0.31mL).By this reaction mixture at room temperature stirred weekend.This reaction mixture is adjusted to pH 5 by adding 1M HCl solution, and solvent is removed under vacuo, to provide 1-[pungent-2-base of 6-(ethoxy carbonyl)-6-azaspiro [3.4]] piperidines-4-carboxylic acid, it is directly used without being further purified.
LCMS (method A): m/z 311 (M+H) +(ES +), at 0.10min, without UV activity.
By 1-[pungent-2-base of 6-(ethoxy carbonyl)-6-azaspiro [3.4]] piperidines-4-carboxylic acid (0.368g, 1.10mmol) be dissolved in DMF (8mL), and add (1-methyl-cyclobutyl) amine hydrochlorate (0.200g, 1.64mmol), HATU (0.458g, 1.21mmol) with DIPEA (0.708g, 5.45mmol).By this reaction mixture under a nitrogen in stirred overnight at room temperature.These solvents are removed under vacuo, and by this resistates at DCM and saturated NaHCO 3distribute between solution, the saturated NaCl solution of organic layer is washed, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 25g, 40-63 μm difficult to understand, 12mL/min; gradient 1% to 8%MeOH is in DCM]); to provide ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl in white foam }-6-azaspiro [3.4] octane-6-carboxylic ester isomer 2 (0.147g, 35.5%).
Data in table 3
approach e
As by example 11, the fluoro-4-of ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl } preparation of-6-azaspiro [3.4] octane-6-carboxylic ester is illustrative, for passing through NaCNBH 3the exemplary program of acid amides is prepared in reduction amination and acyl chlorides coupling
Ethyl-4-fluorine resources-4-carboxylate hydrochloride (0.376g, 1.77mmol) is dissolved in methyl alcohol (5mL), and with the K in minimal amount of water 2cO 3(0.244g, 1.77mmol) process is with desalination.This mixture is concentrated under vacuo, and with methylbenzene azeotropic to dry.This resistates is dissolved in methyl alcohol (10mL), and adds zinc chloride (0.969g, 7.11mmol).This reaction mixture is stirred 2h at 50 DEG C under nitrogen atmosphere, is then cooled to room temperature.Add NaCNBH 3(0.222g, 3.54mmol), and this reaction mixture is spent the night 50 DEG C of stirrings under a nitrogen.This reaction mixture is cooled to room temperature, and these solvents are removed under vacuo, this resistates DCM is diluted, and uses saturated NaHCO 3solution-treated, is filtered obtained multiphase mixture by Celite pad, and this filtrate is used saturated NaHCO 3solution, saturated NaCl solution are washed, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 25g, 40-63 μm difficult to understand, 50mL/min, gradient 1% to 9%MeOH is in DCM]), to provide tertiary butyl 2-[the fluoro-4-of 4-(methoxycarbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.300g, 46%) in colorless oil.
LCMS (method A): m/z 371 (M+H) +(ES +), 1.79 and 1.82min, without UV activity.
There is transesterification under these reaction conditions.
Tertiary butyl 2-[the fluoro-4-of 4-(methoxycarbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.300g, 0.81mmol) is dissolved in DCM (4mL), and adds TFA (1mL).By this reaction mixture under a nitrogen in stirred overnight at room temperature, then these solvents are removed under vacuo, to provide ethyl 1-(pungent-2-base of 6-azaspiro [3.4])-4-fluorine resources-4-carboxylicesters trifluoroacetic acid in deep yellow oily, it is directly used without being further purified.This resistates is at room temperature dissolved in DCM (8mL).Add NEt 3(0.246g, 0.34mL, 2.43mmol) and Vinyl chloroformate (0.176g, 0.16mL, 1.62mmol), and by this reaction mixture under a nitrogen in stirred overnight at room temperature.By this reaction mixture at DCM and saturated NaHCO 3distribute between solution, the saturated NaCl solution of organic layer is washed, and through MgSO 4dry.By this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 10g, 40-63 μm difficult to understand, 12mL/min, gradient 0% to 10%MeOH is in DCM]), to provide ethyl 2-[the fluoro-4-of 4-(methoxycarbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.440g, 158% is impure) in faint yellow oily.
LCMS (method A): m/z 343 (M+H) +(ES +), 1.56 and 1.59min, without UV activity.
At room temperature, ethyl 2-[the fluoro-4-of 4-(methoxycarbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (assuming that 0.81mmol) is dissolved in THF (5mL), and adds 1M LiOH solution (0.81mL).This reaction mixture is at room temperature stirred 2 days.PH is carefully adjusted to pH 6 by adding concentrated hydrochloric acid, these solvents are removed under vacuo, to provide 1-[pungent-2-base of 6-(ethoxy carbonyl)-6-azaspiro [3.4]]-4-fluorine resources-4-carboxylic acid in pale solid shape, it is directly used without being further purified.
LCMS (method A): m/z 329 (M+H) +(ES +), 0.79 and 0.86min, without UV activity.
Thick 1-[pungent-2-base of 6-(ethoxy carbonyl)-6-azaspiro [3.4]]-4-fluorine resources-4-carboxylic acid is suspended in thionyl chloride (3mL), and this reaction is stirred 2h at 90 DEG C.This reaction mixture be cooled to room temperature and concentrate under vacuo.This resistates is dissolved in DCM (5mL), and add (1-methyl-cyclobutyl) amine hydrochlorate (0.196g, 1.62mmol) and DIPEA (0.523g, 0.71mL, 4.05mmol), this reaction mixture is at room temperature stirred spend the night.By this reaction mixture at DCM and saturated NaHCO 3distribute between solution, the saturated NaCl solution of organic layer is washed, and through MgSO 4dry.By this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 25g, 40-63 μm difficult to understand, 12mL/min; gradient 0% to 6%MeOH is in DCM]); to provide the fluoro-4-of ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl in faint yellow glue }-6-azaspiro [3.4] octane-6-carboxylic ester (0.09g; 28%), be the mixture of diastereomer.
Data in table 3
approach f
As by example 14, the preparation of ethyl 2-[4-(t-Butylcarbamoyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester is illustrative, for the preparation of acid amides, carries out the exemplary program of chlorocarbonate coupling subsequently
At room temperature, by ethyl piperidine-4-carboxylicesters (0.35g, 0.32mL, 2.22mmol) and 6-azaspiro [3.4] octane-6-carboxylic acid, 2-oxo-, 1,1-dimethyl ethyl ester (0.500g, 2.22mmol) is dissolved in DCM (20mL), and adds titanium isopropoxide (4.12g, 4.40mL, 14.5mmol).This reaction mixture is at room temperature stirred 1h.Add STAB (0.694g, 0.72mL, 2.44mmol) and acetic acid (0.05mL), and by this reaction mixture at room temperature under a nitrogen stirring spend the night.By this reaction mixture by adding saturated NaHCO 3solution (5mL) cancellation and stir 5 minutes.This reaction mixture DCM is carried out diluting and being filtered by Celite pad.This filtrate is separated and washs by saturated NaCl solution, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 50g, 40-63 μm difficult to understand, 50mL/min, gradient 0% to 5%MeOH is in DCM]), to provide tertiary butyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.739g, 90.9%) in faint yellow oily.
LCMS (method A): m/z 367 (M+H) +(ES +), at 1.94/1.99min, without UV activity
At room temperature, by tertiary butyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.739g, 2.02mmol) be dissolved in THF (10mL), and add 1M LiOH solution (2.02mL).This reaction mixture is at room temperature stirred and spends the night.This reaction mixture is adjusted to pH 5 by adding 1M HCl solution, and solvent is removed under vacuo, to provide 1-[pungent-2-base of 6-(tert-butoxycarbonyl)-6-azaspiro [3.4]] piperidines-4-carboxylic acid, it is not processed in the reaction be used in subsequently.
LCMS (method A): m/z 339 (M+H) +(ES +), at 0.12min, without UV activity
By 1-[pungent-2-base of 6-(tert-butoxycarbonyl)-6-azaspiro [3.4]] piperidines-4-carboxylic acid in DMF (2mL), and add uncle-butylamine (0.087g, 1.20mmol), HATU (0.227g, 0.60mmol) with DIPEA (0.193g, 1.50mmol).By this reaction mixture under a nitrogen in stirred overnight at room temperature.These solvents are removed under vacuo, and by this resistates at DCM and saturated NaHCO 3distribute between solution, the saturated NaCl solution of organic layer is washed, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 10g, 40-63 μm difficult to understand, 12mL/min; gradient 0% to 10%MeOH is in DCM]); to provide the tertiary butyl-2-[4-(t-Butylcarbamoyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.071g, 60.5%) in yellow oily.
LCMS (method A): m/z 394 (M+H) +(ES +), at 1.79min, without UV activity
By the tertiary butyl-2-[4-(t-Butylcarbamoyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.627g; 1.55mmol) be dissolved in DCM (4mL), and add TFA (1mL).By this reaction mixture under a nitrogen in stirred overnight at room temperature, then these solvents are removed under vacuo, to provide 1-(pungent-2-base of 6-azaspiro [3.4])-N-tert-butylpiperidin-4-carboxylic acid amides trifluoroacetic acid (1:2) in oily, it is directly used without being further purified.This resistates is dissolved in DCM (8mL), and adds NEt 3(0.056g, 0.08mL, 0.54mmol) and Vinyl chloroformate (0.024mg, 0.02mL, 0.22mmol), and by this reaction mixture under a nitrogen in stirred overnight at room temperature.These solvents are removed under vacuo, and by this resistates at DCM and saturated NaHCO 3distribute between solution, the saturated NaCl solution of organic layer is washed, and through MgSO 4dry.By this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 10g, 40-63 μm difficult to understand, 12mL/min; gradient 0% to 10%MeOH is in DCM]); to provide ethyl 2-[4-(t-Butylcarbamoyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.027g in pale solid shape; 41%), be the mixture of diastereomer.
Data in table 3
approach g
As by example 13, ethyl 2-{4-[(2-methyl-propyl) formamyl] piperidin-1-yl } preparation of-6-azaspiro [3.4] octane-6-carboxylic ester is illustrative, for being prepared the alternative program of carbamate by acid amides coupling
At room temperature, by ethyl piperidine-4-carboxylicesters (0.35g, 0.32mL, 2.22mmol) and 6-azaspiro [3.4] octane-6-carboxylic acid, 2-oxo-, 1,1-dimethyl ethyl ester (0.500g, 2.22mmol) is dissolved in DCM (20mL), and adds titanium isopropoxide (4.12g, 4.40mL, 14.5mmol).This reaction mixture is at room temperature stirred 1h.Add STAB (0.694g, 0.72mL, 2.44mmol) and acetic acid (0.05mL), and by this reaction mixture at room temperature under a nitrogen stirring spend the night.By this reaction mixture by adding saturated NaHCO 3solution (5mL) cancellation and stir 5 minutes.This reaction mixture DCM is carried out diluting and being filtered by Celite pad.This filtrate is separated and washs by saturated NaCl solution, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 50g, 40-63 μm difficult to understand, 50mL/min, gradient 0% to 5%MeOH is in DCM]), to provide tertiary butyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.739g, 90.9%) in faint yellow oily.
LCMS (method A): m/z 367 (M+H) +(ES +), at 1.94/1.99min, without UV activity
By tertiary butyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (3.00g, 8.20mmol) be dissolved in DCM (40mL), and at room temperature use 4M HCl stirring in diox (10mL) to spend the night.This reaction mixture is concentrated under vacuo, to provide ethyl 1-(pungent-2-base of 6-azaspiro [3.4]) piperidines-4-carboxylicesters trifluoroacetic acid (1:2) in pale pink solid state, it is used in the next step without being further purified.Ethyl 1-(pungent-2-base of 6-azaspiro [3.4]) piperidines-4-carboxylicesters trifluoroacetic acid (1:2) resistates is dissolved in DCM (40mL), and adds NEt 3(2.49g, 3.42mL, 24.6mmol) and Vinyl chloroformate (1.07g, 0.93mL, 9.84mmol), and by this reaction mixture under a nitrogen in stirred overnight at room temperature.These solvents are removed under vacuo, and by this resistates at DCM and saturated NaHCO 3distribute between solution, the saturated NaCl solution of organic layer is washed, and through MgSO 4dry.By this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 50g, 40-63 μm difficult to understand, 50mL/min, gradient 0% to 10%MeOH is in DCM]), to provide ethyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (2.474g, 89%) in orange oily.
LCMS (method A): m/z 339 (M+H) +(ES +), at 1.67/1.71min, without UV activity.
At room temperature, by ethyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (2.474g, 7.32mmol) be dissolved in THF (25mL), and add 1M LiOH solution (7.32mL).By this reaction mixture at room temperature stirred weekend.This reaction mixture is adjusted to pH 5 by adding 1M HCl solution, and solvent is removed under vacuo, to provide 1-[pungent-2-base of 6-(ethoxy carbonyl)-6-azaspiro [3.4]] piperidines-4-carboxylic acid, it is directly used without being further purified.
LCMS (method A): m/z 311 (M+H) +(ES +), at 0.85/0.91min, without UV activity.
By 1-[pungent-2-base of 6-(ethoxy carbonyl)-6-azaspiro [3.4]] piperidines-4-carboxylic acid (0.200g, 0.65mmol) be dissolved in DMF (5mL), add isobutylamine (0.071g, 0.97mmol), HATU (0.270g, 0.71mmol) with DIPEA (0.417g, 3.23mmol).By this reaction mixture under a nitrogen in stirred overnight at room temperature.These solvents are removed under vacuo, and by this resistates at DCM and saturated NaHCO 3distribute between solution, the saturated NaCl solution of organic layer is washed, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 25g, 40-63 μm difficult to understand, 12mL/min; gradient 0% to 10%MeOH is in DCM]); to provide ethyl 2-{4-[(2-methyl-propyl) formamyl] piperidin-1-yl in faint yellow glue }-6-azaspiro [3.4] octane-6-carboxylic ester (0.089g; 37.7%), be the mixture of diastereomer.
Data in table 3
approach h
As by example 25; (2; 2; 2-tri-is deuterated) ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl } preparation of-6-azaspiro [3.4] octane-6-carboxylic ester is illustrative, for being prepared the alternative program of carbamate by the activation of p-nitrophenyl carbamate
At room temperature, by ethyl piperidine-4-carboxylicesters (0.35g, 0.32mL, 2.22mmol) and 6-azaspiro [3.4] octane-6-carboxylic acid, 2-oxo-, 1,1-dimethyl ethyl ester (0.500g, 2.22mmol) is dissolved in DCM (20mL), and adds titanium isopropoxide (4.12g, 4.40mL, 14.5mmol).This reaction mixture is at room temperature stirred 1h.Add STAB (0.694g, 0.72mL, 2.44mmol) and acetic acid (0.05mL), and by this reaction mixture at room temperature under a nitrogen stirring spend the night.By this reaction mixture by adding saturated NaHCO 3solution (5mL) cancellation and stir 5 minutes.This reaction mixture DCM is carried out diluting and being filtered by Celite pad.This filtrate is separated and washs by saturated NaCl solution, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 50g, 40-63 μm difficult to understand, 50mL/min, gradient 0% to 5%MeOH is in DCM]), to provide tertiary butyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.739g, 90.9%) in faint yellow oily.
LCMS (method A): m/z 367 (M+H) +(ES +), at 1.94/1.99min, without UV activity
At room temperature, by tertiary butyl 2-[4-(ethoxy carbonyl) piperidin-1-yl]-6-azaspiro [3.4] octane-6-carboxylic ester (0.739g, 2.02mmol) be dissolved in THF (10mL), and add 1M LiOH solution (2.02mL).This reaction mixture is at room temperature stirred and spends the night.This reaction mixture is adjusted to pH 5 by adding 1M HCl solution, and solvent is removed under vacuo, to provide 1-[pungent-2-base of 6-(tert-butoxycarbonyl)-6-azaspiro [3.4]] piperidines-4-carboxylic acid, it is not processed in the reaction be used in subsequently.
LCMS (method A): m/z 339 (M+H) +(ES +), at 0.12min, without UV activity
By 1-[pungent-2-base of 6-(tert-butoxycarbonyl)-6-azaspiro [3.4]] piperidines-4-carboxylic acid in DMF (5mL), and add (1-methyl-cyclobutyl) amine hydrochlorate (0.37g, 3.03mmol), HATU (0.844g, 2.22mmol) with DIPEA (1.305g, 10.1mmol).By this reaction mixture under a nitrogen in stirred overnight at room temperature.These solvents are removed under vacuo, and by this resistates at DCM and saturated NaHCO 3distribute between solution, the saturated NaCl solution of organic layer is washed, and through MgSO 4dry.These solvents are removed under vacuo, and by this resistates by column chromatography carry out purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 50g, 40-63 μm difficult to understand, 50mL/min; gradient 0% to 10%MeOH is in DCM]); to provide tertiary butyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl in white foam }-6-azaspiro [3.4] octane-6-carboxylic ester (0.627g, 76.7%).
LCMS (method A): m/z 406 (M+H) +(ES +), at 1.81min, without UV activity
By tertiary butyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester (0.747g; 1.84mmol) be dissolved in DCM (8mL), and add TFA (2mL).By this reaction mixture under a nitrogen in stirred overnight at room temperature, then these solvents are removed under vacuo, to provide 1-(pungent-2-base of 6-azaspiro [3.4])-N-(1-methyl-cyclobutyl) piperidines-4-carboxylic acid amides trifluoroacetic acid in deep yellow oily, it is directly used without being further purified.This resistates is dissolved in DCM (10mL), and adds NEt 3(0.56g, 0.77mL, 5.52mmol) and 4-nitrophenyl chlorocarbonate (0.555g, 2.76mmol), and by this reaction mixture under a nitrogen in stirred overnight at room temperature.These solvents are removed under vacuo, and this resistates is distributed between DCM (15mL) and 1N NaOH solution (15mL).By DCM (4x 20mL) extraction of this water layer, through MgSO 4drying, and this solvent is evaporated.By this resistates by column chromatography carry out half purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 25g, 40-63 μm difficult to understand, 25mL/min; gradient 0% to 10%MeOH is in DCM]); to provide 4-nitrophenyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl in yellow colloidal }-6-azaspiro [3.4] octane-6-carboxylic ester (0.60g; 69%), be the mixture of diastereomer.
LCMS (method C): m/z 471 (M+H) +(ES +), at 4.60min, there is UV activity.
Ethanol-2,2,2-d3 (0.186g, 0.22mL, 3.78mmol) to be dissolved in THF (12.6mL) and to be cooled to 0 DEG C.Add sodium hydride (0.202g, 5.044mmol), and stir 1h.Add 4-nitrophenyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl be dissolved in THF (12.6mL) }-6-azaspiro [3.4] octane-6-carboxylic ester (0.600g; 1.26mmol), and by this mixture stir under a nitrogen and spend the night.This mixture is distributed between EtOAc (30mL) and water (30mL).By EtOAc (4x 30mL) extraction of this water layer, through MgSO 4drying, and this solvent is evaporated.By this resistates by column chromatography carry out half purifying (normal phase, [than safe smelting SNAP cylinder KP-sil 25g, 40-63 μm difficult to understand, 25mL/min; gradient 0% to 10%MeOH is in DCM]); to provide the ethyl-2 in yellow colloidal; 2; 2-d32-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester (0.240g; 50%), be the mixture of diastereomer.The separation to diastereomer is realized by preparation HPLC; with provide in canescence glue (2; 2; 2-tri-is deuterated) ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester isomer 1 (0.094g; 39%) isomer 2 (0.085g, 35%) with in canescence glue.
Data in table 3
The synthesis of intermediate:
approach i
As illustrative by the preparation of intermediate 19,1-(the deuterated methyl of 1,1,1-tri-) ring fourth-1-amine hydrochlorate, for the preparation of the exemplary program of amine
Stir in dry ether in the three-necked flask that magnesium (2.67g, 110mmol) is had thermometer and dropping funnel in adaptation.1,1,1-tri-deuterated Methyl iodide (6.24mL, 100mmol) in diethyl ether (40mL) is filled in this dropping funnel, and the minicrystal of iodine is added in this magnesium suspension.By the of short duration heating of this magnesium suspension until iodine staining disperses, but dropwise add the deuterated Methyl iodide solution of 1,1,1-tri-(causing heat release a little).Once complete this interpolation, this mixture is heated to 32 DEG C of lasting 30min, is then cooled to 0 DEG C.Cyclobutanone (5mL, 67mmol) is dissolved in diethyl ether (20mL), filters through dried over mgso.This dropwise is added in this reaction mixture, keep temperature <15 DEG C, then allow to reach ambient temperature overnight.This mixture is distributed between watersoluble chlorinated ammonium (100mL) and diethyl ether (100mL), and extracts 4 times again with ether.By this organic layer through dried over sodium sulfate and concentrated (250 millibars, 40 DEG C), to provide a kind of yellow oil (5.9g, 75%).
1H NMR(300MHz,CDCl 3)δ:1.41-1.52(1H,m),1.60-1.81(2H,m),1.95-2.06(4H,m)。
Chloromethyl cyanide (21.6mL, 340mmol) is added in the solution of 1-(the deuterated methyl of 1,1,1-tri-) ring fourth-1-alcohol (10.14g, 113.7mmol) and acetic acid (3.1mL).This mixture is cooled to 0 DEG C, and dropwise adds the vitriol oil (18.3mL).Once complete this interpolation, allow this solution to reach room temperature and stir 2 hours.This reaction is poured in ice/water (200mL), and extracts with methylene dichloride (3x 150mL).Each organic layer is merged, use sodium carbonate solution (100mL) and salt solution (100mL) washing, also concentrated through dried over sodium sulfate, to provide a kind of yellow oil.By this oil and methylbenzene azeotropic, to provide a kind of beige solid (19.7g, 105%), by its not purified direct use.
1H NMR(300MHz,CDCl 3)δ:1.79-1.90(2H,m),1.99-2.06(2H,m),2.23-2.32(2H,m),3.94(2H,s),6.59(1H,bs)。
By chloro-for 2-N-(1-(1,1, the deuterated methyl of 1-tri-) cyclobutyl) ethanamide (10g, 60.7mmol) and the solution at reflux overnight of thiocarbamide (5.69g, 74.8mmol) in ethanol (45mL) and acetic acid (6.1mL).Allow this reaction mixture is cooled to room temperature and is concentrated to general 22mL.This mixture is added in water (45mL) and also filter to remove precipitation.By this filtrate with diethyl ether (100mL abandons) washing, NaOH (water-based) is then used to alkalize to pH 13.By methylene dichloride (4x 100mL) extraction of this alkaline layer, merge & through dried over sodium sulfate also concentrated (200 millibars, 40 DEG C), to provide a kind of yellow oil (2.08g).This oil to be dissolved in diethyl ether (80mL) and to stir, dropwise making an addition to the HCl in diethyl ether (17mL, 2M) simultaneously.Obtained precipitation is filtered, with diethyl ether, then under vacuo 40 DEG C of dryings, to provide 1-(the deuterated methyl of 1,1,1-tri-) ring fourth-1-amine hydrochlorate (2.35g, 31%).
1H NMR(300MHz,D 2O)δ:1.79-1.89(2H,m),1.98-2.03(2H,m),2.15-2.25(2H,m)。
13C NMR(300MHz,D 2O)δ:13.0,22.5(m),32.0,54.0。
approach j
As illustrative by the preparation of intermediate 20,1-(methyl fluoride) ring fourth-1-amine hydrochlorate, for the preparation of the exemplary program of amine
Under argon gas in room temperature; to (methylsulfinyl) benzene (23.0g; diethylaminosulfur trifluoride (43.0mL is dropwise added in stirred solution 164mmol) in chloroform (80mL); 328mmol); and this reaction mixture is stirred 2 days at this temperature, then spends the night 60 DEG C of stirrings.At 0 DEG C, this mixture is dropwise added in the stirred solution of saturated aqueous sodium bicarbonate, then use dichloromethane extraction 3 times.By the organic layer of merging through dried over sodium sulfate, and concentrated to provide (methyl fluoride) (phenyl) sulfane (20.0g, 86%) in yellow oily.
1H NMR(300MHz,CDCl 3)δ:5.64(s,1H),5.81(s,1H),7.38-7.24(m,3H),7.53-7.46(m,2H)。
At 0 DEG C, to (methyl fluoride) (phenyl) sulfane (20.0g, m-chloroperoxybenzoic acid (84.0g, 475mmol) is partially added in stirred solution 140mmol) in methylene dichloride (300mL).Allow this reaction mixture to be slowly warmed up to room temperature and to be stirred to spend the night.At 0 DEG C, this mixture is poured in the stirred solution of saturated aqueous sodium bicarbonate, then uses dichloromethane extraction three times.By the organic layer washed with brine merged, also concentrated through dried over sodium sulfate, to provide a kind of yellow oil.By this resistates by flash column chromatography purifying (elutriant: heptane: ethyl acetate on silica; 9:1 to 4:1); to provide ((methyl fluoride) alkylsulfonyl) benzene (22.9g, 93%) in yellow oily.
1H NMR(300MHz,CDCl 3)δ:5.05(s,1H),7.63(t,2H),7.73(t,1H),7.97(d,2H)。
By titanium ethanolate (IV) (22.4mL, 107mmol) and cyclobutanone (5.37mL, 71.0mmoL), the mixture in tetrahydrofuran (THF) (120mL) stirs 10 minutes.Add tertiary butane sulfinyl amine (7.17g, 59.0mmol) and this reaction mixture is at room temperature stirred 18 hours.This mixture is concentrated and this resistates is dissolved in ethyl acetate.By the saturated aqueous sodium bicarbonate washing of this solution, also concentrated through dried over sodium sulfate, to provide N-ring butylidene-2-methylpropane-2-sulfinyl amine (9.51g, 77%) in faint yellow oily, by its not purified direct use.
1H NMR(300MHz,CDCl 3)δ:1.18(s,9H),2.12-1.97(m,2H),3.10-3.00(m,2H),3.29-3.11(m,1H),3.52-3.37(m,1H)。
LCMS (method D): m/z 174 (M+H) +(ES +), at 1.10min.
Under argon gas at-78 DEG C to ((methyl fluoride) alkylsulfonyl) benzene (5.0g; n-butyllithium (18.0mL is added in stirred solution 28.7mmol) in tetrahydrofuran (THF) (100mL); 28.7mmol), and this reaction mixture is stirred 40 minutes at this temperature.At-78 DEG C, N-ring butylidene-2-methylpropane-2-sulfinyl amine (3.23g, 18.7mmol) is added in this mixture, and allow this reaction mixture slowly to heat to rt while stirring overnight.By this reaction mixture by adding shrend and go out and with dichloromethane extraction 3 times.By the organic layer washed with brine merged, also concentrated through dried over sodium sulfate, to obtain a kind of brown oil.By this resistates by flash column chromatography purifying (elutriant: heptane: ethyl acetate on silica; 3:2 to 2:3); to provide N-(1-(fluorine (phenyl sulfonyl) methyl) the cyclobutyl)-2-methylpropane-2-sulfinyl amine (3.00g, 33%) in yellow oily.
1H NMR(300MHz,CDCl 3)δ:1.27(s,9H),1.96-1.82(m,1H),2.14-2.00(m,2H),2.38-2.26(m,1H),2.59-2.43(m,1H),2.91-2.76(m,1H),5.04(s,1H),5.53-5.55(m,1H),7.52-7.55(m,2H),7.62-7.65(m,1H),7.93-7.95(m,2H)。
LCMS (method D): m/z 348 (M+H) +(ES +), at 1.54min.
To N-(1-(fluorine (phenyl sulfonyl) methyl) cyclobutyl)-2-methylpropane-2-sulfinyl amine (1.50g; 4.32mmol) in N; sodium acetate (22.6g is added in stirred solution in dinethylformamide (270mL); buffered soln 276mmol) in acetic acid (34.6mL), and by this reaction mixture stirring at room temperature 15 minutes.Add magnesium chips (6.92g, 289mmol), and at 65 DEG C, this mixture is stirred 24 hours.This mixture water and saturated aqueous sodium bicarbonate process are extracted with ethyl acetate 3 times.By also concentrated through dried over sodium sulfate for the organic layer merged, to provide a kind of yellow oil.By this resistates by flash column chromatography purifying (elutriant: heptane: ethyl acetate on silica, 1:1 to 0:1), to provide N-(1-(methyl fluoride) cyclobutyl)-2-methylpropane-2-sulfinyl amine (560mg, 53%) in faint yellow oily.
1H NMR(300MHz,CDCl 3)δ:1.20(s,9H),1.99-1.68(m,2H),3.62(br s,1H),4.36-4.38(m,1H),4.52-4.54(m,1H)。
Under argon gas at 0 DEG C, to N-(1-(methyl fluoride) cyclobutyl)-2-methylpropane-2-sulfinyl amine (1.50g, hydrochloric acid (20mL is added in stirred solution 7.23mmol) in methyl alcohol (20mL), 7.23mmol, in 4M Yu diox), and allow this reaction mixture is heated to room temperature and stirs 1 hour.This mixture is concentrated, and this crude product is ground in diethyl ether and t-butyl methyl ether, to provide desired product 1-(methyl fluoride) ring fourth-1-amine hydrochlorate (0.90g, 90%).
1H NMR(300MHz,CDCl 3)δ:1.92-1.76(m,2H),2.09-1.93(m,2H),2.36-2.16(m,2H),4.54(s,1H),4.70(s,1H),8.68(br s,2H)。
LCMS (method D): m/z 104 (M+H) +(ES +), at 1.31min.
approach k
As illustrative by the preparation of the deuterated ring fourth-1-amine hydrochlorate of intermediate 21,1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4,4-six, for the preparation of the exemplary program of amine
By the propanedioic acid-d4 (165g, 1.53mol) in methylene dichloride (825mL), sulfuric acid-d2 (5.0mL) and first (alcohol-d) (330mL) stirring at room temperature 4 days.Add water-d2 (100mL) and separation of phases.Aqueous phase methylene dichloride (100mL) is heavily extracted.By also concentrated through dried over sodium sulfate for the organic phase merged, to provide a kind of water white oil.By this resistates by distillation purifying (bp:105 DEG C, with 25mmHg), to provide desired product, in colorless oil 2,2-bis-deuterated-dimethyl malonate (161g, 79%).
1H NMR(300MHz,CDCl 3)δ:3.76(s,6H)。
13C NMR(300MHz,CDCl 3)δ:40.7,52.6,167.0。
GC (method F): 20min, at 11.91min, 99.65%.
By this reaction with 2 batches, 80.5g carries out.Under argon gas, lithium deuteride LiD aluminium (40.0g, 0.90mol) partially to be added in anhydrous tetrahydro furan (1.0L) and to be cooled to 0 DEG C.Slowly make an addition in anhydrous tetrahydro furan (300mL) 2,2-bis-deuterated-dimethyl malonate (80.5g, 0.60mol), keep temperature lower than 35 DEG C, and by this reaction mixture in stirred overnight at room temperature.Careful interpolation water (40mL), add sodium hydroxide (40mL, 15% aqueous solution) subsequently, then add other water (120mL), and by this mixture in stirred overnight at room temperature.By this mixture by diatomite filtration, with tetrahydrofuran (THF): methyl alcohol (1:3,1.0L) washs, and this filtrate is concentrated, to provide a kind of thick resistates (76.0g).By this aluminium salt suspension in ethyl acetate: in methyl alcohol (2:1,3.0L), stir 1 hour, filter, and this filtrate is concentrated, to provide thick resistates (126g) a collection of in addition.These two parts of resistatess are merged and pass through distillation purifying, with provide desired product 1,1,2,2,3,3-six deuterated-propane-1,3-glycol (56.0g, 57%).
13C NMR(300MHz,CDCl 3)δ:35.1,57.6,171.0
GC (method F): 20min, at 10.96min, 99.22%.
This reaction is carried out with 2 batches.By N-bromosuccinimide (196g, 1.10mol) partially add 1 to, 1,2,2,3,3-six is deuterated-propane-1,3-glycol (28.0g, 0.368mol) and triphenylphosphine (289g, in solution 1.10mol) in acetonitrile (500mL) and methylene dichloride (500mL), keep temperature lower than 35 DEG C.By this reaction mixture in stirred overnight at room temperature.Add hexane (1L), and each layer will be separated, and heavily extract with hexane (400mL).By the hexane layer sodium hydroxide (250mL, 2M) merged, then wash with saturated water-based S-WAT (200mL), salt solution (200mL), through dried over mgso, and concentrated.By the grinding of this residue with heptanes and by filtering removal solid.This filtrate is concentrated, and by this residue with heptanes second time grinding.Solid is removed by filtering, and filtrate is concentrated from often criticize, to provide crude product (being 44.0g and 34.0g respectively).The resistates merged is passed through distillation purifying, to provide deuterated-1, the 3-dibromopropane of 1,1,2,2,3,3-six (44.0g, 62%).
GC (method F): 20min, at 12.10min, 73.71%.
To sodium hydride (20.3g; 508mmol; 60% is scattered in oil) dropwise add 1,1,2 in cooling suspension in methyl-sulphoxide (450mL) and diethyl ether (110mL); 2; deuterated-1, the 3-dibromopropane (44.0g of 3,3-six; 213mmol) with the solution of p-tosylmethyl isocyanide (33.4g, 171mmol) in methyl-sulphoxide (100mL) and diethyl ether (25mL).This reaction mixture is stirred 15 minutes at 0 DEG C, then heat to room temperature continue 1 hour.In at this moment, solid precipitation, and this reaction mixture is solidified as solid.Add methyl-sulphoxide (200mL), this solid crushing, and this mixture is stirred 3 hours.Careful interpolation water (500mL), by filtering and dry this solid of collection, to provide 1-((the 1-isocyano--2 in brown solid; 2,3,3; the deuterated tetramethylene of 4,4-six) alkylsulfonyl)-4-methylbenzene (41.6g, 80%).By it without being further purified use.
1H NMR(400MHz,CDCl 3)δ:2.46(s,3H),7.38-7.42(m,2H),7.83-7.86(m,2H)。
13C NMR(300MHz,CDCl 3)δ:14.2,21.9,30.8,73.9,129.9,130.6,146.5,164.88。
To 1-((1-isocyano--2; 2; 3; 3; 4; the deuterated tetramethylene of 4-six) alkylsulfonyl) cooling mixture of disposable interpolation sulfuric acid-d2 (9.4mL) and water-d2 (9.4mL) in the solution of-4-methylbenzene (41.6g, 172mmol) in the tetramethylene sulfone (120mL) of distillation.Make this reaction mixture stand high vacuum (using salt of wormwood and potassium hydroxide to catch), and be heated to 120 DEG C.By this product collection in prolong (before pump).This crude product is dissolved in diethyl ether, and will be respectively separated.This organic layer is also concentrated through dried over sodium sulfate, water-bath is remained on 40 DEG C, and pressure is remained on 250 millibars, to provide 2,2,3,3,4, the 4-six deuterated cyclobutanones (5.45g, 42%) in faint yellow oily.
GC (method F): 20min, at 4.93min, 99.03%.
Under argon gas, to magnesium (8.70g, 0.358mol) He in the stirred suspension of iodine (a kind of crystal) in diethyl ether (25mL) add several 1,1, the solution of the deuterated Methyl iodide of 1-tri-in diethyl ether, and by this mixture mild heat 1 minute until color dissipates.To control heat release and to keep the speed of this reaction gentle reflux to add remaining 1,1,1-tri-deuterated Methyl iodide (8.91mL, 0.143mol) in diethyl ether (25mL).After completing this interpolation, by this reaction mixture stirring at room temperature 30 minutes, be then cooled to 0 DEG C., there is heat release during this period to backflow in the solution of the deuterated cyclobutanone (5.45g, 0.0720mmol) of slow interpolation 2,2,3,3,4,4-six in diethyl ether (25mL).This reaction mixture is stirred 30 minutes at 0 DEG C, then stirring at room temperature 30 minutes.By this mixture by the cancellation of careful interpolation saturated water-based ammonium chloride, wash with water (400mL), then diethyl ether (400mL).This aqueous phase diethyl ether (400mL) also extracts by separation of phases.By the organic layer washed with brine merged, also carefully concentrated through dried over sodium sulfate, to provide 1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4,4-six deuterated cyclobutanol (2.42g, 36%).
GC (method F): 20min, at 5.84min, 96.38%.
To 1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4, deuterated cyclobutanol (the 2.42g of 4-six, acetic acid-d4 (7.3mL, 127mmol) and sulfuric acid-d2 (4.2mL is added in cooling and stirring solution 25.4mmol) in 2-chloromethyl cyanide (8.0mL, 127mmol), 76.3mmol), and this reaction mixture is slowly heated to room temperature and stirs 3 hours.This mixture is added in ice, and extracts with methylene dichloride (2x 30mL).By the organic layers with water sodium carbonate solution (30mL) merged, then use salt water washing, also concentrated through dried over sodium sulfate, to provide the chloro-N-of 2-(1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4, the deuterated cyclobutyl of 4-six) ethanamide (3.95g, 91%).
LCMS (method D): m/z 169 (M+H) +(ES +), at 1.04min.
To the chloro-N-of 2-(1-(1,1, the deuterated methyl of 1-tri-)-2,2,3,3, the deuterated cyclobutyl of 4,4-six) add thiocarbamide (7.60g in the stirred solution of ethanamide (8.52g, 48.2mol) in industrial methylated spirits (50mL) and acetic acid (10mL), 99.8mmol), and this reaction mixture is heated to backflow spends the night.Remove solid by filtering, and wash with industrial methylated spirit.In this filtrate, add hydrochloric acid (10mL, 2M), then under reduced pressure remove this industrial methylated spirit.This resistates is distributed between diethyl ether and water.This water layer is basified to pH 10 by adding sodium hydroxide (2M) and extracts with diethyl ether (3x 50mL).By the organic layer of merging through dried over sodium sulfate.Add hydrochloric acid (in 4M Yu diox), and by this mixture stirring at room temperature 1 hour.This mixture is concentrated and uses toluene and azeotropic 3 times, to provide a kind of faint yellow solid.This solid is ground in diethyl ether and drying in vacuum drying oven, to provide the deuterated ring fourth-1-amine hydrochlorate (1.29g, 43%) of 1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4,4-six.
LCMS (method E): m/z 95 (M+H) +(ES +), at 0.92min.
GC (method G): 30min, at 20.56min, 90.57%.
table 2-parent material and intermediate
biologic activity
example A
phosphoric acid-ERK1/2 measures
Use alpha to screen god's fire (the Alphascreen Surefire) phosphoric acid-ERK1/2 mensuration and carry out functional assays (Ke Laoqi (Crouch) & Osmond (Osmond), combinatorial chemistry and high flux screening (Comb.Chem.High Throughput Screen), 2008).ERK1/2 phosphorylation is the downstream events of the protein-coupled receptor activation of Gq/11 and Gi/o, make it highly be suitable for the assessment of M1, M3 (Gq/11 coupling) and M2, M4 acceptor (Gi/o coupling), instead of use different mensuration formats for different receptor subtypes.The Chinese hamster ovary celI of muscarinic for stably express mankind M1, M2, M3 or M4 acceptor is placed in the 96 hole tissue culturing plates of the FBS that (25K/ hole) MEM-α+10% dialyses.Once adhere to, then by cell serum overnight starvation.Agonist stimulation is carried out by adding lasting 5min (37 DEG C) in 5 μ L agonists to these cells.Remove medium and add 50 μ L lysis buffers.After 15min, 4 μ L samples are transferred on 384 orifice plates, and adds the detection mixture of 7 μ L.In the dark, plate is hatched 2h under mitigation is stirred, and then reads plate instrument reads at PHERAstar.
PEC is calculated from the obtained data for each receptor subtype 50and E maxchart.
These be the results are shown in following table 4.
NT=does not test
example B
Passive avoidance
As previously mentioned, the people such as welfare (Foley), (2004) neuropsychopharmacology (Neuropsychopharmacology) is studied.In this passive avoidance task, tropine administrations (1mg/kg, i.p.) in 6 hours after training, make the animal of this example lose the memory of.Before training period, give 90 minutes by oral gavage, checked the dosage range of 3,10 and 30mg/kg (po) free alkali.
Find example 9 isomer 2 with dose dependent fashion with the approximate ED of about 10mg/kg (po) 50reverse the lethe of the tropine induction of this example.The effect of 30mg/kg is similar to the effect (Fig. 1) produced by the anticholinesterase E2020 (0.1mg/kg, ip) serving as positive control.
example C
CA1 cell discharge
At (<4 DEG C) artificial cerebrospinal fluid (aCSF, the composition in mM: NaCl 127, KCl 1.6, KH of freezing mistake 2pO 41.24, MgSO 41.3, CaCl 22.4, NaHCO 326 and D-Glucose 10) in, use vibratome to cut 400 μm of thick rat hippocampal slices.Before electrophysiology record, by (the 95%O of section at oxygenate 2/ 5%CO 2) keep at least 1 hour in room temperature in aCSF, after this, they are transferred to interface chamber, and constantly use the aCSF perfusion of (30 DEG C) oxygenate of temperature with the flow velocity of 1.5-3ml.min-1.Then concentric bipolar electrode stimulating (1-20V, 0.1ms pulse width, 0.033Hz) Schaefer (Schaffer) side shoot is used, to arouse the field excitatory postsynaptic potential (EPSP) (fEPSP) from the radiating layer record in this CA1 region.Carry out testing to check compound compared to 1 μM of carbachol (CCh) to the impact of the amplitude of the fEPSP in the CA1 region of rat hippocampal slices.Initial application 1 μM of CCh, until stable state, washed subsequently before carrying out 5 cumulative concentration-responses to compound.Often kind of compound is tested in 6 sections, and results averaged.Prepared by medicine; By compound dissolution in 30mM in the 100%DMSO of mother liquid concentration; and dilute as required; choline chloride carbamate base choline (CCh) purchased from Sigma (Sigma) (Cat#C4382), and is dissolved in ddH with the mother liquid concentration of 1mM 2in O.
example D
medicament preparation
(i) tablet formulation
By using the compound of 50mg with the 197mg lactose (BP) as thinner and mix as the 3mg Magnesium Stearate of lubricant and carry out in known manner suppressing to form a kind of tablet, prepared and comprised a kind of tablet composition that one has the compound of chemical formula (1).
(ii) capsule preparation
By the compound one of 100mg with chemical formula (1) and 100mg lactose and optionally by weight the Magnesium Stearate of 1% mix mutually, and the mixture obtained is filled in the opaque hard capsule of standard, has prepared a kind of capsule preparation.
equivalent
In order to object of the present invention is described, propose previous examples, and these examples should not form and force any restriction to scope of the present invention.Easily should understand, can multiple modification and change be carried out to the specific embodiments of the invention illustrated in above-described and example and not deviate from cardinal principle of the present invention.All these change and change is all intended to be contained by the application.

Claims (18)

1. one kind has the compound of chemical formula (1):
Or its a kind of salt, wherein:
P is 0,1 or 2;
X 1and X 2be saturated alkyl, these alkyl comprise five to nine carbon atoms altogether together, and link together like this to make with lower part:
Form the loop systems of two rings;
R 1a C 1-10non-aromatic alkyl, this non-aromatic alkyl is optionally replaced by one to six fluorine atoms, and wherein this alkyl one or two but be not that whole carbon atoms is optionally substituted by a heteroatoms, this heteroatoms is selected from O, N and S and oxidised form thereof;
R 2hydrogen or a C 1-10non-aromatic alkyl;
Or R 1and R 2be attached to them together with the nitrogen-atoms on it and form a non-aromatic heterocyclic with four to nine ring memberses, wherein this heterocycle optionally comprises the second heteroatoms that is selected from O, N and S and oxidised form thereof; And wherein this heterocycle is optionally selected from C by one to six 1-2the substituting group of alkyl, fluorine and cyano group replaces;
R 3be selected from hydrogen, halogen, cyano group, hydroxyl, C 1-3alkoxyl group and one are optionally by C that one to six fluorine atoms replace 1-5non-aromatic alkyl, and wherein this alkyl one or two but be not whole carbon atoms be optionally selected from O, N and S a heteroatoms substitute;
R 4a C 1-6non-aromatic alkyl, this non-aromatic alkyl is optionally replaced by one to six fluorine atoms, and wherein this alkyl one or two but be not that whole carbon atoms is optionally substituted by a heteroatoms, this heteroatoms is selected from O, N and S and oxidised form thereof; And
R 5it is fluorine.
2. compound according to claim 1, wherein R 1be selected from:
O is optionally by the C of 1 to 6 fluorine atoms replacements 1-6alkyl;
O is optionally by the methoxyl group-C of 1 to 6 fluorine atoms replacements 1- 4alkyl;
O C 1-6alkoxyl group;
O C 2-6thiazolinyl;
O C 2- 6alkynyl;
O is optionally by C that one or two methyl group replaces 3-6cycloalkyl;
O C 4-5cycloalkyl-CH 2-, wherein this C 4-5cycloalkyl moiety is optionally by a C 1-2alkyl group replaces, and wherein this C 4-5a carbon atom of cycloalkyl moiety is optionally substituted by a Sauerstoffatom;
O cyclopropyl-C 1-3alkyl;
O cyclopentenyl; And
O methyl-two ring [2.2.2] octyl group.
3. according to a kind of compound according to claim 1 or claim 2, wherein R 1be selected from 2-methyl-propyl, 2,2-dimethyl propyl, the tertiary butyl, 2-methyl-Ding-2-base, 2,3-dimethyl butyrate-2-bases, Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl, cyclopentyl-methyl, 1-methyl-cyclobutyl, 1-methylcyclopentyl, 1-methylcyclohexyl, 1-methylcyclopentylmethyl, cyclopropyl-propyl-2-base, 1-methyl-cyclobutyl methyl and 1-ethyl-cyclobutyl methyl group.
4. a kind of compound according to any one of claim 1 to 3, wherein R 2be selected from hydrogen, methyl, ethyl and sec.-propyl.
5. a kind of compound according to any one of claim 1 to 4, wherein R 3be selected from hydrogen, fluorine and methoxyl group.
6. a kind of compound according to any one of claim 1 to 5, wherein R 4be selected from methyl, ethyl, ethynyl and 1-proyl.
7. a kind of compound according to any one of claim 1 to 6, wherein p is 0.
8. a kind of compound according to any one of claim 1 to 7, wherein by the loop systems of two rings formed with lower part:
Be selected from:
(a) azabicyclo-octane or azabicyclo-nonane loop systems;
(b) 2-aza-spiro [3.4] octane or 6-aza-spiro [3.4] octane loop systems; And
(c) pentamethylene pyrrolidine ring system.
9. a kind of compound according to claim 8, wherein by the loop systems of two rings formed with lower part:
Be selected from following loop systems BA, BB, BC, CA, CB and DA:
10. compound according to claim 1, this compound has chemical formula (3):
Wherein R 1, R 3, R 4, R 5with p any one of claim 1 to 7 define; S is 0 or 1 and t is 0 or 1.
11. a kind of compounds according to claim 10, wherein s=0 and t=1.
12. a kind of compounds according to claim 1, this compound is selected from
Ethyl 3-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-8-azabicyclo [3.2.1] octane-8-carboxylicesters,
Ethyl 3-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-9-azabicyclo [3.3.1] nonane-9-carboxylicesters,
Ethyl 3-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azabicyclo [3.2.1] octane-6-carboxylic ester,
Ethyl 5-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl } six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylicesterss,
The fluoro-4-of ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl 6-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-2-azaspiro [3.4] octane-2-carboxylicesters,
Third-2-alkynes-1-base 6-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-2-azaspiro [3.4] octane-2-carboxylicesters,
Ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl (2r, 4s)-2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl (2s, 4r)-2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl 2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl (2r, 4s)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl (2s, 4r)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl 2-(4-{ [the deuterated cyclobutyl of 1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl (2r, 4s)-2-(4-{ [the deuterated cyclobutyl of 1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl (2s, 4r)-2-(4-{ [the deuterated cyclobutyl of 1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl 2-(4-{ [1-(methyl fluoride) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl (2r, 4s)-2-(4-{ [1-(methyl fluoride) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl (2s, 4r)-2-(4-{ [1-(methyl fluoride) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2r, 4s)-2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2s, 4r)-2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl 2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2r, 4s)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2s, 4r)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl 2-(4-{ [the deuterated cyclobutyl of 1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2r, 4s)-2-(4-{ [1-(1; the deuterated methyl of 1,1-tri-)-2,2,3; the deuterated cyclobutyl of 3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2s, 4r)-2-(4-{ [1-(1; the deuterated methyl of 1,1-tri-)-2,2,3; the deuterated cyclobutyl of 3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl 2-(4-{ [the deuterated cyclobutyl of 1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2r, 4s)-2-(4-{ [1-(1; the deuterated methyl of 1,1-tri-)-2,2,3; the deuterated cyclobutyl of 3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl 2-(4-{ [the deuterated cyclobutyl of 1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl 2-(4-{ [1-(methyl fluoride) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2r, 4s)-2-(4-{ [1-(methyl fluoride) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2s, 4r)-2-(4-{ [1-(methyl fluoride) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl 2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl (2r, 4s)-2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl (2s, 4r)-2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl 2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl (2r, 4s)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl (2s, 4r)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl 2-(4-{ [the deuterated cyclobutyl of 1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl (2r; 4s)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-)-2,2; the deuterated cyclobutyl of 3,3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl (2s; 4r)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-)-2,2; the deuterated cyclobutyl of 3,3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester.
13. a kind of compounds according to claim 12, this compound is selected from
Ethyl (2r, 4s)-2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl (2r, 4s)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl (2r, 4s)-2-(4-{ [the deuterated cyclobutyl of 1-(the deuterated methyl of 1,1,1-tri-)-2,2,3,3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
Ethyl (2r, 4s)-2-(4-{ [1-(methyl fluoride) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2r, 4s)-2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2r, 4s)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2r, 4s)-2-(4-{ [1-(1; the deuterated methyl of 1,1-tri-)-2,2,3; the deuterated cyclobutyl of 3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2r, 4s)-2-(4-{ [1-(1; the deuterated methyl of 1,1-tri-)-2,2,3; the deuterated cyclobutyl of 3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(2,2,2-tri-is deuterated) ethyl (2r, 4s)-2-(4-{ [1-(methyl fluoride) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl (2r, 4s)-2-{4-[(1-methyl-cyclobutyl) formamyl] piperidin-1-yl }-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl (2r, 4s)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-) cyclobutyl] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester,
(1,1,2,2,2-five is deuterated) ethyl (2r; 4s)-2-(4-{ [1-(the deuterated methyl of 1,1,1-tri-)-2,2; the deuterated cyclobutyl of 3,3,4,4-six] formamyl } piperidin-1-yl)-6-azaspiro [3.4] octane-6-carboxylic ester.
14. a kind of compounds according to any one of claim 1 to 13, for using in medicine.
15. 1 kinds of pharmaceutical compositions, this pharmaceutical composition comprise a kind of any one of claim 1 to 13 the compound that defines and a kind of pharmaceutically acceptable vehicle.
16. a kind of compounds according to any one of claim 1 to 13, have muscarinic M1 receptor agonist activity.
17. as herein any one of embodiment 1.1 to 1.82,2.1 to 2.29,3.1 and 4.1 to 4.3 the invention that defines.
18. according to a kind of compound described in claim 1 to 13, for treatment cognitive disorder or psychotic disorders or treatment or reduce acute, chronic, nervosa or inflammatory pain severity in use.
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